Good morning. Welcome to the 2021 Alkermes Investor Day, and thank you for joining us. I'm Sandy Coombs, Vice President of Investor Relations. I hope you find today's presentations informative. During today's presentations, we will be making forward looking statements based on our current expectations relating to, among other things, the company's future financial and operating performance the potential therapeutic and commercial value of nembleukin and our other product candidates advancement of our research and development programs and our value enhancement plan and broader corporate strategy.
These forward looking statements are neither promises nor guarantees and are subject to a high degree of uncertainty and risk. Please see Slide 2 of the investor presentation accompanying this webcast and our most recent annual report filed with the SEC for important risk factors that could cause our actual performance and results to differ materially from those expressed or implied in the forward looking statements. We undertake no obligation to update or revise the statements provided on this webcast as a result of new information or future results or developments. Our presentations will include recent data from certain ongoing clinical trials in our ARTISTRY nembleukin alfa. The data set will evolve as patient enrollment continues and as more patient data becomes available.
And the data presented today may not be indicative of future data from such trials or results of future trials. Following today's presentation, our panelists will be available for Q and A. Please use the question bar at the bottom of the webcast player to submit your questions at any time during the presentations or during the Q and A session. Now, I'd like to welcome Richard Pops, Alkermes' CEO, who will tell you more about what you can expect to hear today.
Good morning. The purpose of today's presentation is to prompt a fresh look at Alkermes. The timing of the presentation is driven by the timing of the business. New developments are maturing in the commercial portfolio, in the development portfolio and in the way we run the business. You're going to hear a lot of new things today.
And if there's only one thing that I'd like you to take away from my brief introduction, it's the intense focus we have on building the value and the valuation of Alkermes through the powerful combination of both scientific and business excellence. The way we create value in biopharmaceutical companies is by making important medicines, medicines that bring new value to patients in the healthcare system. Making these types of medicines requires sophisticated and complex scientific capabilities and we have that at Alkermes. But the way we can enhance that value and make it rewarding to shareholders is by an equivalent focus on optimizing the way we run the business, focusing on structure, efficiencies and profitability. So today, we're going to spend some time on each of these.
Alkermes is a rare company in the biopharmaceutical industry. We have a substantial and growing business with a portfolio of approved drugs, established drug development and commercialization capabilities and a $1,000,000,000 top line. That is the here and now. You'll hear more today about what's coming next, promising future growth opportunities based on new neuroscience and oncology product candidates in development. This is all coupled now with a focus on profitability, cost management and disciplined governance.
Our revenues are driven by a diverse portfolio of growing products that target large markets. VIVITROL is the only long acting antagonist approved to treat patients with opioid and alcohol dependence. ARISTADA is a long acting injectable antipsychotic well positioned for continuing growth with this differentiated once every 2 month dosing regimen. And we have the potential for new and growing revenue streams with expected launch of our second antipsychotic in our portfolio, LOVALVI and the anticipated growth of VUMERITY, a drug for the treatment of MS that we developed and it's being sold by Biogen. As you'll see today, the value of our pipeline and our R and D investment is beginning to emerge.
The most prominent element in the pipeline is nimvalukin, which is emerging as a highly differentiated immuno oncology agent. You'll hear important updates on that program today and it by itself may drive a reconsideration of the value of Alkermes pipeline. We'll also discuss other new candidates that are advancing in development. Each program is designed to address specific unmet needs in neuroscience and oncology, leveraging our scientific strengths. We've been successful in developing new medicines in the past and we fully expect to continue to do so.
In its simplest form, the investment thesis is very clear. A substantial current business and an exciting future driven by compelling science and a focus on profitability and efficient management of the business, scientific excellence paired with business excellence. In a few minutes, Blair will focus in on the business side of the equation. I want to spend a few minutes now to explain how the scientific side has evolved. Our R and D strategy has evolved significantly.
In what I would call our legacy strategy, we chose targets based on our assessment that we could add significant value to known existing drug molecules through our formulation, prodrug and drug delivery technologies. This approach had many virtues, including the ability to move rapidly to late stage development. It was also quite successful, yielding a portfolio of important medicines used to treat people living with serious and complex diseases and that serve as the foundation of our $1,000,000,000 revenue base. Along the way, we've developed new technical capabilities and identified opportunities for capturing even more value from our R and D efforts. Our new R and D strategy has evolved over the past 2 years.
Its effectiveness is now becoming clear to us, which is why this is an appropriate time to provide some additional insight and reveal some of its results. In contrast to our legacy approach of looking to add value to existing medicines, we're now entirely focused on creating new molecular entities to address unmet patient needs. It's a pretty simple calculus. New molecules addressing unmet needs have the potential to drive more value. The new strategy is characterized by focus and management.
We're focused in 2 key therapeutic areas, neuroscience and oncology. Within these fields, we further concentrated our efforts and you'll hear more about that later in the day. Consistent with our legacy strategy, we choose targets based on well validated biology, no longer to the extent of previously approved medicines, but in areas where we believe that if we can design a molecule with the right properties, it will function in a manner we can generally anticipate. That leverages our established strengths in molecular design. This is where we've proven expertise.
ARISTADA, Umeriti and Semidorphin are new small molecules with intellectual property developed by Alkermes Chemists in challenging chemistry spaces. Nembolukin is an engineered polypeptide designed by Alkermes Molecular Biologists. Our goal is to focus on programs that are focused on designing new molecules based on established biology rather than testing new biological hypotheses and then aggressively managing these programs in order to maximize the return on our R and D investments. We utilize an integrated approach to evaluating targets and programs, incorporating inputs from across the company. We do this on an ongoing basis to gauge our scientific, competitive, commercial and intellectual property standing.
We try to design each development sound, this approach is not always aligned with more traditional drug development processes and often requires new thinking and new translational tools. We rely on data to prioritize. We recognize that there is a virtue to prioritization and allocation of resources within a bounded R and D budget. It forces objective assessment of what's moving at the right speed with high potential and what is not. So, summarized in the box on the right is where we built and continue to build scientific excellence, applying our expertise to develop novel molecules to target unmet needs in neuroscience and oncology.
The value enhancement plan is focused on establishing complementary business excellence. We introduced the plan in December of last year to make explicit our intention to drive increasing efficiency and profitability. The plan establishes clear profitability goals for 2023 2024, which we intend to reach by managing to whichever revenue trajectory that we are on. It provides a framework for allocating capital and prioritizing investments in our major cost areas of commercial and R and D. And it drives an intense focus on programs with the highest expected return on investment.
It incorporates feedback from shareholders, external advisors and peer group benchmarking data. Our commitment to business excellence is summarized in the box on the right with management and governance at the board level all focused on growth, efficiency and profitability. The combination of scientific excellence and business excellence drives enterprise value. It's a powerful concept that we've incorporated now into all aspects of the way Alkermes operates And it's what will drive our ability to grow value in the future. This approach reinforces the core purpose and values that animate our employees, our collaborators and other shareholders and stakeholders.
What we do is important for many people, great science, deep compassion, real impact. We pursue these goals in a collaborative, respectful and inclusive culture inspired by a patient focused mission that we're passionate about. So let's move then to today's agenda. It's broken into 4 blocks. In the first, Blair Jackson, our COO, will outline our focus on creating value.
Blair, along with Ian Brown, our CFO, have been the principal architects of operationalizing the value enhancement plan. They bring great clarity and focus to the business. Next, Craig Hopkinson, our Head of R and D and Chief Medical Officer and Marcus Haverlein, our Head of Research will explain their approach to R and D at Alkermes. I think you'll see that they bring a very pragmatic management philosophy, one focused on rapid decision making and progress toward clearly articulated goals. We'll then move into the specific programs beginning with oncology.
We'll start with nemba leuka. Jessica Rege runs clinical oncology for us. She is an experienced oncology drug developer and she'll share with you her perspectives on the program and important new updates, including monotherapy efficacy in Artistry 1 and a significant new milestone, which is the first response in our Artistry 2 subcutaneous program. She'll be followed by Heather Lohse, a PhD scientist who leads the group that designed nimvelu can. Her team's work anticipated clinical successes we're seeing as monotherapy and in combination.
And their ongoing preclinical work is expected to continue to light the path for expanding indications. And then Josh Heiber, one of our another of our PhD scientists will introduce you for the first time to another engineered cytokine for cancer, our tumor targeted split IL-twelve program. From there, we'll move to neuroscience. Marcus will return to discuss our HDAC inhibitors for synaptic dysfunction, including our first clinical candidate in ALKS 1140. Brian Raymer, a PhD Senior Scientist will discuss for the first time our Orexin program.
After the presentations, we'll go into Q and A. So we have a lot to cover. And with that, we'll get started.
Thanks, Rich. I'm Blair Jackson, the Chief Operating Officer of Alkermes. And I've been with the company since 1999 having served in various capacities over the years, with the most recent as the Head of Corporate Planning. My top priorities are ensuring operational excellence, efficiency in our activities and implementation of the value enhancement plan. As Rich highlighted, Alkermes is at an exciting point in its evolution.
Today, we will discuss many of our innovative and cutting edge research programs and capabilities in both neuroscience and oncology, which we believe will create significant value for the organization. Before we get there, I wanted to spend a few moments discussing the broader Alkermes business. As a company, the building blocks are in place for value creation for our shareholders. Our goals outlined clearly in our value enhancement plan are based on expansion of the top line through growth of our existing portfolio of revenue generating assets. With recently launched and potentially new products expected to provide our next leg of growth.
It's based on the careful management of our costs by efficiently allocating capital only to those programs that we believe will generate a high return and are aligned with the long term strategy of the organization. This discipline coupled with aggressive spend management are important elements of our strategy to meet the profitability targets set forth in our value enhancement plan, growing our non GAAP net income margin from 7% in 2020 to 25% by 2023 and 30% by 2024. These dynamics are complemented by strong corporate governance, including significant Board refreshment over the last 2 years. Our board is highly experienced and actively engaged in ensuring the success of Alkermes. Let's take each of these elements in turn.
Starting first with the top line, our revenues are generated by a portfolio of commercial products serving large markets. This is a platform that we've been building over the last few years. In 2020, we generated over $1,000,000,000 in annual revenue from products sold by both Alkermes and 3rd parties. Our investments in the development of new innovative medicines has dramatically shifted the complexion of our revenue profile over the last 5 years from a company highly dependent on partnered products to one where proprietary products contribute the majority of revenues. With the potential launch of Libolvi, we anticipate that we will continue to see the proportion of proprietary revenues grow.
We're focused on 4 key growth drivers. These are highly differentiated products, each with their own independent market dynamics, all targeting large commercial markets and with long expected patent lives, providing us with a strong platform for future growth. The first two products, VIVITROL and ARISTADA, generated over 550,000,000 in 2020. Both brands are growing with patent coverage extending for a significant period of time. Next, Libolvii and VUMERITY are poised to contribute potential growth to our top and bottom line.
Top line growth arising from expanding revenues as these products launched into large established markets. Bottom line growth due to our ability to leverage our existing commercial infrastructure for the expected launch of Libolvii and due to VUMERITY revenues driven by royalties generated by our commercial partner, Biogen. I would like to spend a few moments on each of the growth drivers of the company. First, VIVITROL, approved for alcohol dependence and the prevention of relapse to opioid dependence following detoxification. From 2015 to 2019, we saw a 23% cumulative annual growth rate that was interrupted by the COVID crisis, which impacted patients' abilities to receive treatment.
It's important to recognize that both the alcohol and the opioid dependence indications contribute to VIVITROL's growth profile, although they each have their own unique characteristics. Interestingly, the alcohol dependence indication has grown at a significantly faster rate than the opioid indication over the last 5 years. As I mentioned, the disruption caused by COVID-nineteen broadly impacted patients' ability to access the healthcare system for treatment. This restriction impacted VIVITROL use due to the requirement for injections, the need to be opioid free before receiving treatment, which often requires detoxification in a medical setting and the unique nature of substance abuse treatment settings of care. The VIVITROL commercial team immediately worked to adapt how they did business to support patients and healthcare providers in this new environment.
Within a few months, we began to see the product stabilize and begin to recover. Within the alcohol dependence market, we've seen a resumption of growth, while within opioid dependence, we still see disruptions, primarily related to settings of care that have yet to fully increase their patient capacity, most notably residential treatment centers, correctional facilities and other government treatment locations. We anticipate that VIVITROL volume will regain growth as access to care improves in the second half of twenty twenty one. Next, we have ARISTADA approved for schizophrenia. We've seen a 50% cumulative annual growth rate for this product since 2016 with minimal impact from the COVID crisis.
This strong performance has a great deal to do with ARISTADA's characteristics. Physicians have responded well to the range of doses and treatment options available using ARISTADA. One dosage form that has stood out is the 2 month 10/60 4 mg dose. We've seen the use of this dose increase by 50% in 2020 alone as physicians recognize the benefit of the less frequent dosing interval, especially in situations where there's limited patient contact. This positions the product well within the $3,500,000,000 long acting injectable market.
ARISTADA currently holds a 9% share based on months of therapy and has seen growth rates that well exceed the broader LAI class, 16% in 2020 versus 5% for the class as a whole. Our commercial team is working to build upon this success as they execute their 2021 business plans. Next, we have Libolby, which will be our newest product for the treatment of schizophrenia and bipolar I disorder, pending approval from the FDA. The PDUFA date for this product is June 1 this year and we anticipate launching in the second half of the year. Libolvii is designed to offer the efficacy of llanzapine while mitigating its potential weight gain.
The results from our ENLIGHTEN-two study were clear In a 561 person Phase 3 6 month study comparing olanzapine to Libolpi, it was demonstrated that the mean weight gain is 57% higher with olanzapine versus Libolvii and that risk of clinically meaningful weight gain was twice as high if the patient was on olanzapine than if they were on Libolpi. We believe Libolpi, if approved, will represent an important medicine for the treatment community. Olanzapine is widely recognized as being highly efficacious, but physicians and patients avoid prolonged utilization due to concerns about its propensity for weight gain. For Alkermes, this is also an important product. It will demonstrate the leverage of our business model since the existing commercial organization that sells ARISTADA can be leveraged to also sell LYVOLVY, allowing Alkermes to launch into 2 new therapeutic areas with a relatively lower spend than we would need otherwise had that existing infrastructure not been in place.
This will help drive margin expansion for our existing commercial products and will allow the Volvie to potentially be accretive in the 2nd year of launch. With a planned launch later this year, our teams are actively preparing to engage with payers and physicians following the potential approval. Libolvii will compete in 2 large markets, oral schizophrenia treatment and oral bipolar 1 disorder treatment. This is largely a generic market, but one where branded agents can still be successful due to the serious unmet needs that remain. Branded agents in these markets exceed $3,000,000,000 annually.
Across the oral atypical market, there are over 30,000,000 prescriptions per year. Interestingly, Olanzapine is having a resurgence as physicians move towards more efficacious molecules, seeing a 15% growth rate year over year for new to brand prescriptions. This has resulted in olanzapine market share of 21% for oral schizophrenia prescriptions and 12% for oral bipolar 1 disorder prescriptions. Our market research underscores the perceptions around olanzapine and unmet needs. The majority of surveyed health care providers agree that olanzapine is one of the most efficacious oral antipsychotics for schizophrenia and bipolar 1.
At the same time, weight gain is a major concern for these patients that can often be a cause for these patients to discontinue treatment. This is a highly dynamic marketplace with over 70,000 treatment switches occurring each month as patients look for the right medication to fit their needs. We believe that many physicians will recognize the benefits that Libolvi can potentially provide to their patients. Finally, we have VUMERITY, a next generation fumarate that we developed for the treatment of multiple sclerosis. We partnered with Biogen and are fully responsible for the commercialization of this product.
With a 15% royalty on net sales, VUMERITY provides a significant high margin revenue growth driver for the company. Despite Biogen launching during the COVID-nineteen crisis, we have recently seen an inflection in monthly TRx data, an early sign of the product's acceptance. Our existing commercial product revenues provide a strong base with the potential for continued long term growth. VIVITROL is anticipated to deliver $315,000,000 to $345,000,000 of revenue this year. And ARISTADA is anticipated to deliver $260,000,000 to $290,000,000 of revenue.
We believe that VUMERITY is at the front of its growth curve and we anticipate that it together with Libolbi once approved will drive significant revenue in the coming years, providing that next leg of growth. So we've tackled the revenue portion of the profitability equation. Now we will discuss the cost side, our focus on organizational efficiency and cost management. In order to support our profitability initiatives, late last year and into the beginning of this year, we and our external advisors conducted a thorough review of our cost structure with the goal of identifying potential areas of efficiencies and savings. This was a comprehensive exercise that involved benchmarking our resource utilization with companies in our competitive set and consisted of both external spend and headcount.
We took a careful look at our growth strategy and the resources required to achieve these goals, and we critically assess the need for in house capabilities versus outsourcing. We identified a number of opportunities to streamline our processes and reduce expense, and we've been moving quickly. Some of these were implemented into our 2021 plan and were already reflected in the guidance we gave earlier this year, and some will be implemented as we go forward. Some key initiatives are the realignment of the commercial infrastructure to put additional emphasis on alcohol dependence in the case of VIVITROL, the reallocation of resources within the psychiatry franchise to support an efficient Libolby launch, prioritization of our development portfolio and the shifting of some of our activities to an outsourcing model. All of these changes will have an immediate impact on the business and will shift the long term spending profile of the organization.
When it comes to capital allocation, we're strongly focused on ensuring that we're allocating our capital to the highest ROI opportunities that are consistent with our long term growth strategy. Our priorities are clear: support our commercial portfolio to drive top line growth work to ensure the approval and launch of Libolvii to provide the additional growth driver, advanced nimvelukin to drive value through elaborating the clinical opportunity and to facilitate potential partnering discussions and develop our next generation of pipeline candidates. This is a balance of driving future growth through innovation, while growing our operating margins.
For our
existing commercial portfolio, we're focused on supporting the continued growth of our brands. For VIVITROL, we've optimized our field force efforts and marketing spend to ensure maximum coverage of the value opportunities in both the alcohol and opioid businesses. For ARISTADA, we're leaning into the success we saw late last year through clear messaging around the benefits of ARISTADA and ensuring that the teams have adequate support to meet their sales and marketing initiatives for 2021. For the Libolbi launch, it's about ensuring strong execution. We've optimized our psychiatry infrastructure to facilitate the sale of both ARISTADA and LYVOLVY by the same field team.
We are ensuring that we have the sales team in place and that the appropriate market access activities and materials are ready for the anticipated launch. Additionally, we're funding ongoing clinical activity that was designed to augment our clinical data set and to support those studies that are required as part of our potential approval. When it's all taken together, due to the leverage of the existing infrastructure and some of the efficiency programs that we discussed earlier. We expect our SG and A spend to increase by approximately $50,000,000 despite the fact that we'll be launching this new product into 2 large therapeutic areas, demonstrating the leverage that we've built into our commercial business. With memvelukin, our spend is focused purely on elucidating the potential clinical effects of this product, demonstrating both IV and subcutaneous efficacy responses in multiple tumor types through both our ARTISTRY-1 and ARTISTRY-two program.
Additionally, you will see today some of the latest data that's been generated in this program and following responses that we've already seen in our Artistry 1 program, The challenge and the opportunity with nimble glucan is that there's a wide range of potential treatment settings that may benefit from this agent. We've carefully streamlined our program to ensure that we're focusing our limited resources on studies that we believe will provide the best dataset to support our partnering efforts and to support fast to market opportunities. Finally, we're investing to support our early pipeline candidates that we'll be discussing today. These products have the potential to provide future growth drivers for the company. But as with anything that's in early stage, these come with some risks, and we've implemented a robust stage gate process to ensure that these potential development candidates meet pre established R and D and commercial requirements before we invest in larger clinical trials.
We believe that the combination of near term revenue growth with aggressive cost management will position the company to meet the goals that we've put forward for 2023 2024. In moving from a non GAAP net income margin of 7% currently to 25% by 2023, we're actively managing 3 key areas of the business. First, our commercial business, maximizing individual product contribution, driving revenue while keeping costs tightly contained. 2nd, research and development, prioritizing our spend to only high ROI programs, rigorously applying our stage gate evaluations and continuing with our efficiency initiatives. 3rd, G and A and operations, continuing to identify and implement operational efficiencies and eliminating costs where possible.
Within each of these areas, we have a number of different levers and the relative contributions of each could change depending on the results of our business. We're managing the company in such a way that we can achieve our targets in a wide range of business scenarios. Another facet to our plan is the careful assessment of assets within the company to look for potential untapped value. We're taking a careful look at our long term strategy and assessing how all of our programs and assets fit to support these goals. We're looking for opportunities to monetize our non core assets and we will be exploring strategic oncology collaborations, starting first with the nemfalukin program as that data begins to mature.
Some of the items that have been and will continue to be explored are providing access to our platforms and intellectual property to 3rd parties as well as the licensing or divesting of preclinical or clinical assets that are outside of our current long term strategy. Additionally, we are evaluating a number of financial options that are available to us, such as monetizing our royalty streams or entering into risk sharing product development structures. It's important to highlight that these activities can take some time and may be dependent on future data or market conditions. A core element to Alkermes is our strong corporate governance. We work to ensure that we've established best practices with regards to Board structure, Board membership and management compensation.
We've assembled a strong group of directors with a diversity of experience and deep backgrounds in science, finance, corporate strategy and operations, areas of focus key to the advancement of our strategy. We have actively refreshed the Board in an effort to ensure expertise that furthers our strategic focus with numerous Board additions over the last few years, and we continue to focus on Board refreshments in 2021. The Board is actively involved in the value enhancement plan, providing oversight through the Financial Operating Committee and incorporating important aspects of the plan into the company's 2021 short term and long term incentive plans. Over the last 2 years, we've added 4 new members to the Board of Directors, David D'Aglio, Brian McKeon, Andy Wilson and Richard Gaynor, as part of our long term refreshment program. These new directors bring strong operational, financial and oncology expertise.
Our Board representation fits perfectly with our focus on profitability, commercial and operational execution as well as advancement of our neuroscience and oncology strategies. Alkermes' combination of significant diverse revenues, our emerging pipeline and a focus on profitability creates a unique and compelling investment opportunity. Our commercial business is generating over $1,000,000,000 of revenue and is poised for additional growth with new and growing products. Our oncology and neuroscience programs are highly differentiated and designed to address significant unmet clinical needs. We will be hearing a great deal more about these programs over the course of the day, and I'm confident that you will find Alkermes' combination of science and business excellence has the potential to drive significant near term value.
Good morning. I'm Craig Hopkinson, Executive Vice President of Research and Development and Chief Medical Officer here at Alkermes. Throughout my 25 years in the industry, I have advanced the development of large and small molecules in therapeutic areas with broad applicability such as oncology, but also in orphan disease states. The companies I've worked at have ranged from organizations with vast resources dedicated to research and development such as Pfizer, Eisai and Vertex as well as smaller companies that demanded prioritization of investments such as Actelium and Alarm. Since I joined Alkermes almost 4 years ago, my focus has been on establishing a pragmatic process and continuing to cultivate a strong culture centrally focused on developing novel medications that advance the standard of care and bridge unmet need for the patients that we serve.
Today, you will hear from our team a number of specific examples of our new R and D approach in action. However, before we get to that, I wanted to spend a minute on the philosophy behind our R and D strategy and judicious approach to management of our programs and resources. Our objective is to develop truly innovative medicines with a clear value proposition relative to the current and anticipated future standards of care in neuroscience and in oncology. We do this through the discovery of new molecular entities with a strong biologic rationale. Today, you'll learn about our scientific platforms and advanced capabilities in areas such as molecular design and protein engineering that serve as the foundation of our R and D strategy.
We seek to drive efficient execution and cost management with a rigorous fully integrated governance process utilizing pre specified success criteria to ensure that we are continuously validating both the medical and economic benefits of our programs as they advance through the product development lifecycle. As we seek to develop truly innovative medicines, we emphasize the importance of integration, starting with the target selection and continuing throughout the product development lifecycle. Understanding how our program fits into our portfolio strategy as well as the competitive landscape and our commercial footprint is critical from ideation onwards. Next, in contrast to Alchemy's legacy approach, which was based on innovation through formulation and delivery technologies, everything we are now doing is focused on novel molecular entities, leveraging our advanced medicinal chemistry and protein engineering capabilities to deliver 1st in class or best in class medications to our patients. So if the molecule is the hardware, the innovation we bring to our processes and the methodologies we utilize to advance these medications is the software.
Our development approach is designed to de risk our programs and investment by asking and answering the critical questions of our target product profile as early as possible to drive our decision making. A fundamental aspect of this is the use of forward and reverse translational medicine strategies. In essence, bringing the bench closer to the bedside known as forward translational medicine by establishing proof of pharmacology and target engagement as early as possible and also bringing the bedside closer to the bench with Reverse Translational Medicine to drive understanding of the disease biology and identify the patient populations most likely to derive benefit from our therapies right from the start of development. These strategies can then be used to select targeted patient populations and help inform the most impactful endpoints to test our clinical program. So on this slide, you can see what we mean by an integrated approach.
The way we define a high value development candidate is not just by looking through a single lens, but by adopting a multifaceted approach in the assessment of our programs. It starts with ensuring that there's a strong biologic rationale and unmet need. From there, we evaluate the probability of success, not just technically with respect to chemistry, but also to understand if there are established clinical and regulatory pathways to achieve our target product profile. Understanding the commercial opportunity incorporates a thorough competitive assessment and differentiation strategy evaluation. It is only by understanding each of these domains collectively that one can truly understand the impact and value opportunity of a new potential medication.
And as our molecules advance through the various stages of development, these domains are continuously utilized to measure progress at defined stage gates as well as to assess return on investment for potential target product profile expansion or lifecycle management opportunities. The most critical aspect of efficient drug development is ensuring that you are interrogating and addressing the key critical questions to assess the target product profile as early as possible. We employ targeted methodologies across our preclinical and clinical R and D programs to expedite data driven decision making. During preclinical development, we conduct studies in disease relevant models to demonstrate biologic proof of concept. Today, you'll see how we employed this approach with our Orexin program.
In that program, we tested our differentiation strategy in multiple preclinical models such as the rat pharmaco EEG, a hemodynamic as well as a DTA mouse narcolepsy model. We conduct thermomelectular design feasibility and process chemistry efforts to expedite readiness for clinical Phase 1 studies. In clinical development, we utilize innovative clinical trial designs such as the basket study approach we plan to utilize for ALKS 1140 to accelerate generation of critical data and to support both advancement of the program as well as indication prioritization. In addition, we partner early with regulators to establish clear and expeditious regulatory pathways for our programs. We're also judicious in the allocation of our R and D resources.
This is not just theoretical. Our cross functional governance and pre established stage gates are working as they were intended. For each of these programs you see here, there could have been an argument to advance them if you were simply looking through one of the lenses in our evaluation process that I outlined earlier on. However, by having a fully integrated governance process and pre established success criteria across the full target profile, it enables stronger portfolio prioritization assessment and quicker decision making, allowing for resources to be redeployed to programs with greater potential and economic benefit. And the final key component, cross validating our strategy by incorporating critical ongoing external assessments.
Now we do this through 2 mechanisms. First, we have a dedicated neuroscience and oncology scientific advisory board comprised of world leading experts to provide ongoing independent assessment across our programs. In addition to meeting collectively to review areas across the pipeline, they also engage routinely with our teams to address emerging challenges within the programs. 2nd, through the establishment of disease specific clinical advisory board meetings, we gather external insights into our clinical trial designs, regulatory pathway and differentiation strategy assessments. So in closing, as you can see, our newly designed approach to R and D is focused on developing innovative medicines and ensuring that we maximize our probability of technical, regulatory and commercial success through a disciplined multifaceted approach to drug development.
1st and foremost, we initiate design and execute our research and development programs based on a clear medical and economic value proposition. This is about delivering new first in class or best in class treatment options for patients, not just designing a new molecule. 2nd, we accelerate time to data through elements such as sophisticated translational medicine plans, proactive regulatory interaction strategy pathways and robust execution. And lastly, we stay focused and objective through a cohesive vision by pre specifying clear success criteria, following the data and making the tough decisions when needed. These are foundational principles as we seek to efficiently develop truly innovative medicines with a clear value proposition for patients with unmet need and drive value creation.
Thank you very much for your attention.
Good morning. I'm Markus Haberlein. I'm Head of Research at Alchemists and I've been with the company for 5 years. My background is in medicinal chemistry and molecular modeling. I very much enjoy the challenge of solving a difficult drug design problem and to use predictive methods to improve the odds of generating better medicines.
I started my career at AstraZeneca, where I spent 15 years and ended up as Head of Medicinal Chemistry and Chair of AstraZeneca's Global Chemistry Leaders Network, where I was responsible for the global chemistry strategy and its implementation. This included building an industry leading capability in predictive chemistry. From AZ, I made the move into biotech and became CSO of Proteostasis, where we worked on neurodegenerative and orphan diseases. So let us now dive into what we do at Alchemists. You will see that molecular design is at the forefront.
So our research strategy is focused on projects where we can apply our innovative molecular design in both medicinal chemistry and protein engineering. The projects we pursue have a strong biology rationale and are often technically challenging. We are carefully selecting targets based on a range of factors shown on the left and also described by trade earlier. Looking at the right hand side, let us now go a bit deeper into the biology rationale of our programs. So we have built up a strong biology capabilities within defined scientific platforms.
Our targets have internal and external validation and are vetted with our scientific advisors. We prioritize targets with the potential opportunity to be 1st in class and or best in class. And finally, we need to have a structure activity insight that guides our novel molecular design. So this is important for us and you will see several examples of this during the course of the day. On the technical feasibility end, we are driven by clear design strategies to address technical challenges.
Here, we utilize our integrated technical capabilities in medicinal chemistry, protein engineering and molecular modeling. Our key philosophy is to utilize what we believe is the best approach, tool or technology in medicinal chemistry or protein engineering for a given target. In medicinal chemistry, we have a strong computational support, which we coupled with a significant synthesis expertise. This enables us to expand our accessible chemistry space to difficult to synthesize molecules. We have set up strategic collaborations, which give us access to modern chemistry toolbox.
And examples are protein degraded technology and DNA encoder libraries. On the protein engineering side, we do also have a close integration with our modeling team to guide our protein design. And we have spent the last few years building up advanced protein engineering capabilities with a broad toolbox. In the subsequent presentations, you will see examples of cytokine reengineering, how we're using our proprietary tumor targeting platform in novel ways and application of bispecific fusion proteins. We have built a state of the art modeling capability to support our small molecular and biologics projects.
This includes advanced molecular dynamics simulations, quantum chemical calculations, artificial intelligence and proprietary machine learning models to guide our design. The machine learning models can be seen as an in silico assay panel, where we can get predictions of how our molecular design ideas will perform in in vitro assays, such as potency, metabolic stability and safety related assays. So this means that before we even have synthesized the molecule, we have a good feel for its performance and if it's worth making. At the center of the slide, you see our proprietary internal medicinal chemistry design tool, which we call ALKSketch. Within this tool, our medicinal chemists can draw a molecule and get instant feedback on the predicted performance.
They can add an atom or remove an atom and immediately see if the predictive properties are improved. In summary, we have a sophisticated molecular design toolbox that enables us to address challenging targets. Let us now move to the scientific platforms where we are applying this toolbox. Within our 2 therapeutic areas, we have focused our biology capabilities and expertise on 2 scientific platforms with broad potential in the indication space. These are synaptic dysfunction in neuroscience and immune modulation in oncology.
Within neuroscience, we have a long standing presence in psychiatry, which has recently expanded to include opportunities in neurology. Within oncology, we have built on our platform capabilities in engineered cytokines, which led to the development of Nemalu can. I will now describe those platforms in a bit more detail. I would also give you a brief overview of the projects we have in our research portfolio and some of these projects we have not shown before. Let us start with looking closer at the synaptic dysfunction platform.
Synaptic loss is currently the best pathologic correlate with cognitive decline. Therefore, improving synaptic function is critical to slow progression and preserve cognitive and functional abilities in neurological disorders. So we are targeting the synaptic integrity and function at different levels. Structurally, we want to restore the integrity and number of synapses. Functionally, we want to restore the efficiency of synapses and the circuitry.
And finally, we want to improve on the efficiency of supporting cells, such as microglia and astrocytes. So let us now look at the projects we are pursuing in this area. We are currently advancing 4 programs in neuroscience. So let us start with our HDAC inhibitors, where we have 3 programs in the neuroscience field. In our 2 most advanced programs, ALKS1140 and its follow on molecule, we're pursuing Co REST selective HDAC inhibitors, which are prosynaptic.
And further, we have an HDAC program where in addition to improving Synapse Health, we are seeking to increase the production of proganalin. So I will go deeper into the HDAC program in a later session. So this is the first time we're talking about our orexin 2 receptor agonist program. Our orexin agonists are designed to restore the abnormal neurotransmission resulting from loss of orexin producing neurons. We plan to apply these molecules toward narcolepsy and indication with excessive daytime sleepiness, fatigue or attention and cognition issues.
And Brian will give you more details of our Orexin II agonist program. So let us now move on to our oncology portfolio. In the area of immune modulation, we have initially focused on pro inflammatory cytokines. They have pleiotropic effects and can act virtually on every phase of the cancer immunity cycle. Alchemists is focusing on cytokine based therapies designed to increase the visibility of tumor cells to the immune system, increase the tumor killing potential of CD8, T and NK cells, remove suppressive signals in the tumor microenvironment And more than cytokine based drugs, they need a high degree of engineering to reduce their side effects, improve their pharmacokinetics and enhance their efficacy.
Our portfolio of engineered cytokines is maturing and we have 3 programs, which are highly differentiated from each other. They're all based on a different design approach. And each approach is best suited for that particular cytokine. So, let us start with our most mature project, nemvelukin alfa, which is in Phase 2. Here we created a molecule that only activates the intermediate affinity IL-two receptor and thus selectively expands tumor killing CD8 T cells and NK cells, while having a minimal expansion of the tumor suppressing Treg cells.
So you will hear more about the research end of this program from Heather and an update on the clinical program from Jessica. So let us now move to IL-twelve in the middle column. This is the first time we show our IL-twelve program. IL-twelve is one of the most potent inflammatory cytokines, but is suffering from a very low systemic tolerability. The challenge here is to have enough efficacy in the tumor, but avoiding severe systemic side effects.
So our solution is to build the IL-twelve molecule in the tumor in vivo. We're doing this by administering the 2 IL-twelve subunits separately and have them assemble in the tumor using a proprietary tumor targeting moiety. And Josh will give you more details on this approach. Our newest program in this family is IL-eighteen, as you see on the right. IL-eighteen has potent anti tumor properties, but is limited by the upregulation of a checkpoint protein known as IL-eighteen binding protein, which blocks the effect of IL-eighteen.
So we are engineering an IL-eighteen protein, which is not blocked by tumor suppressing mechanisms. So we plan to share more details about this program at a later date. So these 3 cytokines all have different mechanisms, as you see from the downstream signaling, and others also positioned towards different indications. So now let us have a look at the summary of our overall project portfolio. With focus and discipline, we have built up a research portfolio in both neuroscience and oncology.
We believe we are now well positioned to deliver a steady stream of meaningful differentiated molecules, which are based on a strong biology rationale. And this concludes the overview section and we will now move on to highlight some of our projects. We will start with my colleague, Jessica Regin, who will give a clinical update on our most advanced cytokine engineering program, nemvelukin alfa. Jessica, please.
Hello. My name is Jessica Rege and I'm the Head of Oncology Development here at Alkermes. I recently joined Alkermes after building a small startup biotech and consulting company. I'm a PhD by training with over 15 years of oncology drug development in the industry. I have held leadership roles in R and D at major oncology companies such as Lilly and Eisai.
I'm delighted to speak to you all today about the nimbleukin alpha program. During today's presentation, I'll outline the potential of harnessing the IL-two pathway and the important differentiation features of the nimbleukin program, both in terms of the molecule itself and our approach to developing this drug in the clinic. Then I will update you on how some of this differentiation has translated to the accumulating data sets from our ARTISTRY I and ARTISTRY II clinical studies. We have exciting new developments here. In the ARTISTRY-one IV program, we are seeing new and deepening responses using nimvelukin as both monotherapy and in combination with pembrolizumab in hard to treat tumors.
And we are moving ahead aggressively in mucosal melanoma platinum resistant ovarian cancer. We are also thrilled to be able to report our very first response in the ARTISTRY-two subcutaneous program, following the recent selection of the recommended Phase 2 dose. This progress has reinforced our excitement about the program and is informing our clinical development strategies. Let's start with why I'm so excited about this program and why I came to Alkermes to lead it. IL-two is a natural regulator of immune response.
Expansion of cancer killing cells can heighten the body's natural immunologic response to various tumor types and the efficacy of many cancer treatments depends on the robustness of this response. Recombinant human IL-two was one of the first immuno oncology agents. It is an effective treatment, demonstrating both complete and durable responses in a select tumor types, but significant toxicity limits its broader use. A new molecule with differentiated tolerability could be complementary to a wide range of therapeutic approaches. This is exactly what nimvelu can is designed to do.
Our approach is consistent with the way our cancer treatments have evolved over time. Think about it. Toxic non specific chemotherapies have been revolutionized by deeper biologic and genetic understanding, which yielded specific targeted agents. We set out to transform a natural cytokine IL-two into our modern immuno oncology agent. How did we accomplish this?
This leads me to the novel design of nimbilukin and how our scientists here at Alkermes selectively engineered the molecule. Nimbleukin was designed to retain the therapeutic benefits of recombinant human IL-two by selectively activating anti tumor effector cells shown by the blue cells on the right, while mitigating the IL-two associated expansion of the immunosuppressive regulatory T cells. Nimbleleukin is a stable fusion protein consisting of IL-two in the alpha subunit of high affinity IL-two receptor. As shown here on the right, the design allows nimvelu can to preferentially bind to the intermediate affinity IL-two receptor, located on the CD8 T cells and NK cells, which are both important cells in fighting cancer. At the same time, with this design feature, we've been able to sterically occlude nimbilukin from binding to the high affinity receptor, which has been associated with the undesirable effects of IL-two.
Pimvalukin is administered as an inherently active drug, it does not require any metabolic conversion and does not degrade to native IL-two. In order to confirm the differentiated profile of nimbilukin from other IL-two variant approaches, we set out clear objectives in our development program. First, we needed to validate the molecular design features by demonstrating the dose dependent selective expansion of NK and CD8 T cells with a nominal expansion of Tregs. This was first confirmed with our intravenous administration and more recently with subcutaneous, which I will elaborate on later in the presentation. 2nd, we needed to demonstrate that the immunological response could translate into anti tumor activity.
From our perspective, monotherapy anti tumor activity is essential to validating the potential therapeutic benefit of nimvelu can. Today, I will share an update on the accumulating monotherapy response data and also activity we've seen in combination with pembro, all in hard to treat tumors. Lastly, we had a goal of dosing flexibility. Nimvelukin is the only IL-two variant with a subcutaneous administration option in development. We recently identified the recommended Phase 2 dose for subcutaneous and have observed our first objective response in the dose expansion phase of the study.
I'll share more on that later. Together, these features are designed to support the broad potential use of this compound. So now, let's discuss how we plan to take these important differentiation features of our molecule and build a clinical development strategy that is unique from our competitors. Our clinical development strategy is clear, focused on the unmet needs of patients with difficult to treat cancer. In this figure, we are contrasting 2 different approaches.
The one on the left, the strategy would be to add our drug to standard of care, seeking to improve it. But informed by the profile of nimbleukin we are now merging in the clinic, we decided to adopt the different approach depicted by the circles here on the right. Patients with tumor types where checkpoint inhibitors are either not approved or patients that have been on checkpoint inhibitors and have progressed. These are patients where the standard of care has failed and treatment options are limited. So specifically within these circles, we plan to advance nimvelukin in combination with pembro in platinum resistant ovarian cancer or PROC, which is a tumor type where PD-one inhibitors are not approved and have failed in the clinical setting.
We also plan to advance nimvelu can as monotherapy for patients with mucosal melanoma following failure on a checkpoint. These strategies may allow us to expedite our development programs, since we are focused in areas of clear unmet need. Now, let's deep dive into the data that underpins this strategy. Let me start with the ARTISTRY I, our IV dosing study. ARTISTRY I has provided us with a lot of critical early data.
In this study, we have seen combination activity with pembrolizumab in multiple different tumor types, both approved and unapproved indications for checkpoint inhibitors. Although I will not be presenting that data today, we look forward to sharing it at future medical meetings. For today, I will be focusing on our monotherapy antitumor activity in melanoma and combination activity in ovarian with pembrolizumab. First, let's look at our monotherapy responses today. Demonstration of monotherapy anti tumor activity is essential to validating the potential therapeutic benefit of nimvelu can, both as a single agent and also when used in combination with other agents.
Shown in this slide are the monotherapy responses that we've seen thus far with IV nimvelu can. We've seen responses in both renal cell carcinoma and melanoma, both mucosal and now cutaneous in all of these patients who have progressed on prior PD-one or PD L1 treatment prior to joining our study. As of mid March, we have seen 3 objective responses in melanoma and 2 in renal cell carcinoma. We are encouraged by these responses and are focusing our initial efforts towards melanoma. Let's talk about the safety profile and what we've seen thus far with the Artistry 1 program.
It is consistent with our design hypothesis. Most commonly reported AE with monotherapy IV treatment were chills, pyrexia and hypotension, the majority of which were transient in nature and low in grade. Nimbleleukin given in combination with pembrolizumab did not demonstrate any additive toxicity or require additional dose modifications to that established with pembro alone. We've treated over 150 patients. And you can see here, the side effect profile across the monotherapy and combination cohorts was generally consistent with anticipated effects of cytokine administration and minimal dose modifications.
Now, let's shift our focus to melanoma. Melanoma is a 5th most common cancer in the United States with cutaneous melanoma being the most common. Mucosal melanoma is a rare and more aggressive type of melanoma with a poor prognosis of only 14% 5 year survival rate. And in most cases, this disease is caught late and in the advanced stages and is largely resistant to traditional treatments. Response rates are low for both chemotherapy and immune checkpoint inhibitors and are even lower as patients progress through multiple lines of therapy, including checkpoint inhibitors.
Nimvelukin was recently granted orphan designation for mucosal melanoma. Now, let me share some important updates with you from our melanoma monotherapy cohort. First, let's begin by sharing key elements of the study design for the monotherapy arms. The monotherapy cohort for this study were designed to target a population where clear unmet need. To enter the study, the patients must have been previously treated with a checkpoint inhibitor and or a targeted agent as appropriate and progressed on that therapy.
The monotherapy portion of the study was set up as a SIMON 2 stage in which if we established 2 responses in the first stage, we would open the 2nd stage. In the latter part of the year, we achieved 2 responses, opened the 2nd stage and expanded the enrollment in the melanoma cohort. Now let's look at the recent data cut of the melanoma patients treated thus far. Swimmers plot shows the overall responses as noted by the yellow boxes and the duration of those responses shown in each of the swim lanes. This is an early look at the data.
We've enrolled a total of 37 patients, but only 28 have at least 1 post baseline scan and are shown here. As you can see, the data are still quite immature as noted by the shorter swim lanes and the green arrow noting the green arrows noting that patients are still ongoing. As expected, the majority are cutaneous melanoma patients, but we do have a handful of mucosal melanoma included in this plot. The 2 mucosal melanoma responders shown in the top lane and in the 4th lane down were previously reported at ESMA. But today, we're sharing a new monotherapy response in cutaneous melanoma as noted by the patient identified by the blue arrow.
We are encouraged by this early activity we are seeing in the monotherapy cohort and look forward to presenting more data at upcoming congresses. Now let's focus our attention on the new response in the cutaneous melanoma patient. There is a narrative of the patient that is a 67 year old male who was originally diagnosed in 2016. He underwent surgery followed by 9 months of adjuvant treatment with a MEK inhibitor and a PD L1 inhibitor. The patient relapsed and was again re challenged with an additional checkpoint inhibitor with the best overall response of progressive disease.
He then went on to have a short courses of chemo and a vaccine before enrolling into ARTISTRY-1 and initiating treatment with nimvelukin in December of 2020 last year. His first scan showed a notable tumor reduction of 27%, which recently deepened to 44% reduction at his second scan, achieving a partial response by RECIST criteria. The patient did have low grade fever and anemia and intermittent Grade 3 and Grade 4 neutropenia without fever. This patient remains on treatment and we await potential confirmation of the response at the next planned scan. Our monotherapy development strategy is clear and focused as we advance towards registration.
We are encouraged by the data in monotherapy in melanoma and CPI experienced patients, which is an area of significant unmet need. The recent orphan designation is an important milestone for the nimbleukin program and underscores nimvalukin's potential clinical utility in mucosal melanoma. Based on these data, we plan to engage the regulatory authorities on a potential path to registration in mucosal melanoma and CPI experienced patients and plan to initiate a melanoma study to support that potential registration. Now that we've talked about the monotherapy strategy, I want to shift gears and talk about our combination strategy in PD-one unapproved tumor types. Starting with the platinum resistant ovarian cancer, a tumor type with a significant unmet need in which we've seen responses thus far in combination with pembrolizumab.
As we think about the treatment landscape for ovarian cancer, the standard of care for first line treatment is multi modality involving both surgery, platinum based chemotherapies with or without bevacizumab and PARP inhibitor. It is important to note that there are no anti PD-one or PD L1 treatments approved for ovarian cancer. Following first line platinum based chemotherapy, patients may become resistant and their disease often progresses within 6 months. Unfortunately, there are limited treatment options for these patients with platinum resistant ovarian cancer. The median overall survival for platinum resistant ovarian cancer is less than 12 months.
The standard of care non platinum chemotherapy has low response rates and is associated with short progression free survival of only about 3.5 months. Given the high unmet need for these patient populations, we are encouraged by the data thus far we've seen in platinum resistant ovarian cancer. Here is a recent swimmer's plot of the ovarian cancer patients treated in ARTISTRY 1. Shown here are 14 ovarian cancer patients with at least 1 post baseline scan. Patients had a median of 4 prior lines of treatment.
And overall, we now have 4 responses noted by the gray and yellow boxes, one complete response and 3 partial responses. In addition, the patient noted by OC5 has had stable disease for over a year now. The data continued to mature from our data cut last presented at SITC in November. We have one new responder OC4 noted by the blue arrow, which I will talk more about in a minute. But before that, let's take a deeper dive into the 5 patients in which we've seen some tumor reduction thus far.
All of these 5 patients received prior platinum based chemotherapy and were assessed by the investigators as platinum resistant. Some had also received prior bevacizumab and or a PARP inhibitor and these five patients, 4 patients experienced an objective response, 1 confirms complete response and the rest partial responses. In addition, as I noted prior, OC5 had stable disease with a total tumor shrinkage of 28%, right on the cuff of 30%, which would be required for a partial response per RECIST. All of these patients have shown deepening and durable responses. Notably, the patient with the complete response just passed 2 years of treatment and remains on the study.
Additionally, patients with partial response have been on treatment for over a year. Now let's talk more about the deepening and durable responses for the recent new responder OC4. Here is the patient narrative. The 75 year old female with high grade serous ovarian cancer previously treated with both platinum and non platinum based chemotherapies. She also received both PARP and bevacizumab.
After multiple lines of therapy, she initiated combination treatment with nimbleukin and pembrolizumab. As you can see here by her tumor shrinkage data, early on this patient showed initial tumor shrinkage at 22% on her first two scans and then additional shrinkage down to 28% reduction. This remained for an additional 6 cycles. Most recently at cycle 14, almost 1 year into treatment, the patient showed an additional tumor reduction to 34%, which by RECIST is a partial response. She has tolerated treatment well with transient grade 3 elevation in liver enzymes and anemia and she remains on treatment.
We continue to be encouraged by the deepening in durable responses in platinum resistant ovarian cancer and plan to build upon these results in an upcoming trial. Based on these data and the significant unmet need, we are continuing to advance our fast to market strategy in platinum resistant ovarian cancer. Looking ahead, we plan to advance our discussions with the FDA regarding a potential path to registration and plan to initiate a study later this year in combination with pembrolizumab. Now let's shift gears to subcutaneous to our subcutaneous dosing study, ARTISTRY-two, where we've recently observed the first partial response in combination with pembrolizumab and it's also in a patient with platinum resistant ovarian cancer. ARTISTRY-two is our subcutaneous dosing study.
We recently identified 3 mg qweekly as our recommended Phase II dose and opened our Phase II expansion phase of the study. The recommended Phase 2 dose was selected based on the totality of data from the dose escalation phase of the study, which included pharmacokinetics, pharmacodynamics, safety and anti tumor activity. Based on these data, we also believe that 6 mgs Q3 weekly dosing regimen may offer additional flexibility as a dosing alternative in certain tumor types and or combination regimens that we may pursue in the future. Today, I will provide an overview of the dose escalation data, but a more complete data set will be presented at an upcoming medical Congress. Based on the selection of the recommended Phase 2 dose, we've recently opened the efficacy expansion cohorts.
First, let's talk about the safety data that supported the recommended Phase Both the 3 mgs qweekly and the 6 mgs q3 weekly demonstrated an acceptable safety profile with anticipated cytokine treatment related adverse events. We selected 3 mg weekly dosing as our recommended Phase 2 based on some of the pharmacodynamic data and to further focus the program. The safety profile was consistent with the previously reported safety profile from the IV dosing. The most common AEs were fever, chills and injection site reactions, all were lower in grade in transient in nature. There were no treatment related SAEs, discontinuations or deaths.
6 mgsqweekly10 mgsq3weekly were deemed as the maximum tolerated dose as these patients experienced either DLTs or a dose reduced to manage adverse events more frequently. We saw 3 dose limiting toxicities during the expansion phase at the maximum tolerated dose, including an atypical case of capillary leak syndrome without hypotension in a heavily pretreated non small cell lung cancer with previous pleural effusions noted. Overall, at the recommended Phase 2 dose, the safety profile of subcutaneous nimvelu can was consistent with the mechanism of action and the safety profile we've previously seen with the IV nimbleukin dosing. Shown here are the pharmacodynamic data, which demonstrated dose dependent selective expansion of circulating NK and CD8 T cells with minimal expansion in the Treg cells. Shown are the max fold changes of each of the relevant PD markers of CD8 T cells, NK cells and Tregs all the way on the right.
The blue bars are the 2 subcutaneous dosing of 3 mgs qweekly and 6 mgs q3 weekly. And the green bars are the previously reported IV data. An MK and CD8 T cell expansion achieved by both subcutaneous regimens were near equivalent or greater compared to that of the IV recommended Phase 2 dose of nimboleukin. There were minimal non dose dependent changes in Tregs. The data demonstrated an enhancement of circulating NK and CD8 T cells with an approximately 16 fold and 3 fold expansion at the subcutaneous 3 mgs qweekly dosing.
Importantly, the expansion of NK cells with this subcutaneous dose exceeded that seen with the IV dosing. Several studies have shown the significance of NK cell expansion in the ability to induce direct tumor killing. Based on the totality of the safety data and the pharmacokinetic and pharmacodynamic data, we selected for ARTISTRY II study the recommended Phase II dose of 3 mgs qweekly to move forward in our expansion cohorts in combination with pembrolizumab. Enrollment in the selected solid tumor dedicated cohorts began in January. The primary objective of the Phase 2 expansion is to evaluate the safety and efficacy of the combination.
Today, I'm happy to share the first response from the expansion phase. Here is the patient narrative. A 69 year old female platinum resistant ovarian patient with high grade serous histology. In addition, the relevant markers for her disease of PD L1 positive and BRCA negative are noted here. She was previously treated with platinum based chemotherapy and relapsed within 6 months, followed by treatment with a PARP and a BEV, including another course of Doxil and BEV in which she rapidly progressed.
She began treatment in January of this year with a combination of nimveluukin and pembrolizumab. Baseline tumor burden is shown here with an overall 200 millimeter total target lesions, which reduced by 50% at the first post baseline scan. From RECIST, this is a partial response. Also notable were her CA125 marker response, which decreased from 1900 down to 300 and almost 84% reduction in tumor marker. She remains on treatment and has tolerated therapy well.
AEs of low grade hypotension and dehydration and multiple grade 1 injection site reactions were noted. This first demonstration of anti tumor activity with our subcutaneous dosing is an important milestone for the ARTISTRY II program. We are encouraged by the progress we have made. We are now at the stage where we are enrolling patients at therapeutic doses across a wide range of tumors and we are expected to continue to accumulate data across all of these studies and plan to present the data at upcoming congresses. We are focused on advancing our interactions with regulatory authorities for both mucosal melanoma and platinum resistant ovarian cancer and advancing towards registration enabling studies as fast as we can.
We believe that nimbleukin's potential broad utility, including the dosing flexibility will enable us to support discussions as we pursue strategic collaborations to further expand our development program. Now, I'll hand the presentation over to Heather, who will discuss the preclinical data that will further enhance our development programs moving forward.
My name is Heather Lohse and I'm the research program lead for nemvelukin alpha. I joined Alkermes in 2011 with a background in protein engineering and design to help establish the growing efforts in protein therapeutics discovery. It was in our group that the hypothesis and design of nymphalukin originated. I'm happy to be here today to share with you the ongoing preclinical research on nemvelukin aimed at supporting the continued expansion of the clinical development program. You heard from Marcus how our research portfolio of engineered cytokines has expanded beyond nembilukin.
Jessica already walked through the high level design principles of nemvelukin, leveraging protein engineering approaches to selectively activate the intermediate affinity IL-two receptor expressed on tumor fighting CD8 T cells and NK cells and avoiding undesired activation of the high affinity IL-two receptor, which is predominantly expressed on immunosuppressive regulatory T cells and vascular endothelial cells. Beyond our ongoing clinical trials, we continue significant research focused in maximizing the understanding of nemvelukin, leveraging scientific rationale to prioritize combination approaches with complementary mechanisms of action. Before I walk you through the ongoing research efforts, I want to take the time to orient you to some of the principles of tumor surveillance by the immune system. There is typically some level of immune activation as a result of tumor formation and growth. Tumors accumulate mutations and other abnormalities over time that can lead to immune activation.
These mutations lead to the development of certain mutated proteins also known as tumor specific antigens that are expressed on the tumor cell surface and also may be released from dying tumor cells. These tumor specific antigens can be picked up by antigen presenting cells, which can then activate T cells as well as other immune cell populations like NK cells, which are known to attack tumors as well. Endogenous IL-two among other cytokines is a key mediator of aiding the immune system activation and immune mediated tumor cell death. In the case of advanced cancer, the immune response is many times not robust enough to keep tumor growth in check. The goal of IL-two based immunotherapy and other immunotherapies is to harness the body's immune system to amplify the anti tumor immune response leading to enhanced tumor cell death.
The goal of tumor directed cancer therapies like those listed on this slide is of course to lead to tumor cell death. Many types of therapies do this, but some therapies are better at that are recognized by the immune system as a trigger for an immune response. Immunogenic cancer cell death happens when dying tumor cells release tumor specific antigens that are recognized by the immune system as a trigger for an immune response. Many types of oncology therapies can induce immunogenic cancer cell deaths, many times as a result of cellular stress responses. Agents that lead to increased cell death have a higher chance of driving tumor antigen release from dying cancer cells.
As mentioned before, these tumor specific antigens can be picked up by antigen presenting cells like dendritic cells, which activate T cells to attack other similar cancer cells to further augment tumor cell death. You already saw in the clinical overview section that nemvelukin has shown evidence of monotherapy activity in melanoma and renal cell carcinoma and thus nemvelukin is able to drive immune mediated anti tumor activity in patients as a single agent, likely due to its amplification and activation of cancer fighting CD8 T cells and NK cells. This leads to immune mediated tumor cell death. Building on the observed monotherapy activity of nimvelu can, there is great potential for complementary synergistic activity between nemvelukin and standard of care therapies that results in immunogenic tumor cell death and increased tumor antigen release driving new T cell activation. In concert with nemvelukin, which can augment the resulting immune response, The hypothesis is that the net result would be further enhancement of tumor killing with durability of that response because of resulting anti tumor immunity.
Before I walk you through the emerging nembleukin combination data, I'll tell you about the evolution of the program and how we got to where we are today. After designing the molecule, our early preclinical work established that the design of nemvelukin as a fusion between circularly permuted IL-two and IL-two receptor alpha led to the intended results. We confirmed that nemphaleukin showed the intended selectivity for the intermediate affinity IL-two receptor, resulting in selective expansion of CD8 T cells and NK cells relative to Tregs, which has subsequently been demonstrated in our ongoing clinical studies as well. Some of the earliest combination studies we carried out were with the immune checkpoint inhibitors, which established the early clinical development plan in combination with pembrolizumab. You heard the promising clinical results to date both with monotherapy antitumor activity and activity in combination with pembrolizumab.
These results have led to seek potential registrational paths in mucosal melanoma using monotherapy nemvelukin and in platinum resistant ovarian cancer in combination with pembrolizumab. The oncology treatment landscape has been built on a foundation of combination therapies. Because of this, a significant portion of our current preclinical efforts are focused on identifying particular anticancer therapies that have mechanisms complementary to nemvelukin. This is intended to guide the directions for the expansion of the nemvelukin clinical development program. As you heard in this section's introductory slides, we have focused on particular molecular mechanisms that lead to immunogenic cancer cell death based on the scientific rationale for complementarity with nemvelukin's mechanism of action.
The main classes of therapies for discussion today include immune checkpoint inhibitors, growth factor pathway inhibitors, certain types of chemotherapy and radiation. Each of these therapeutic classes are known inducers of immunogenic cancer cell death. Immune checkpoint inhibitors have emerged as foundational approaches in cancer immunotherapy. As just shared during the nembleukin clinical update, the combination of nembleukin with pembrolizumab and anti PD-one antibody demonstrated multiple objective responses in a number of tumor types, including those that don't typically respond robustly to monotherapy immune checkpoint inhibition. The nembleukin clinical development strategy in combination with pembro was accelerated based on some of our earliest efficacy studies in mice testing nemvelukin in combination with anti PD-one and we have additional positive preclinical data in combination with anti CTLA-four, data that would support additional combination immunotherapy strategies.
Moving beyond immune checkpoint inhibitors to another oncology therapeutic class that has been shown to induce immunogenic cell death, growth factor pathway inhibitors including small molecule multi tyrosine kinase inhibitors and the more selective growth factor antagonists like anti VEGF. There are a number of growth factor pathways that tumors can harness to provide a survival advantage. Angiogenesis or new blood vessel formation is a pathway that tumors frequently leverage to enhance nutrient delivery, but growth factors can also enhance tumor growth and metastasis in other ways. Therefore, blocking growth factor pathways has proven to be a validated approach for treating many tumors, leading to reduced tumor growth and metastasis, decreased tumor angiogenesis and increased immune cell trafficking to the tumor microenvironment. Inhibition of growth factor signaling culminates in driving immunogenic cancer cell death, release of tumor antigens and thus new T cell activation and nembleleukin mediated immune activation may further augment the anticancer immune responses triggered by these inhibitors.
In order to assess the mechanistic complementarity of growth factor pathway inhibitors with nimbleukin, we looked in tumors of mice treated with the mouse version of nimbleukin and the multi tyrosine kinase inhibitors lenvatinib and lucitanib. Both multi TKIs are known to potently inhibit angiogenesis as well as a number of other growth factor receptors. These types of analyses may allow us to elucidate potential biomarkers of response to nemvelukin or to combination therapy with nemvelukin. In this particular set of data exemplified with the lucitanib combination, we characterize the immune cells and tumors to assess how the treatments shifted the balance of immune activation and immune suppression in the tumor microenvironment. The addition of nemvelukin to lucitanib significantly expanded cancer fighting CD8 T cells and dendritic cells in a dose dependent manner.
These effects on both CD8 T cells and dendritic cells support the interplay of immunogenic cancer cell death from lucitanib, releasing tumor antigens allowing dendritic cells to drive new T cell responses, which can then be enhanced by nemvelukin's ability to activate and expand CD8 T cells. There were also decreases observed nembleukin treated mouse tumors as well as a robust decrease in the numbers of tumor associated macrophages after monotherapy nembleukin, which was even further enhanced in the combination treated animals. Tumor associated macrophages have also been linked to immune suppressive activity in tumors. Very similar observations have been demonstrated with the lenvatinib combination as well. Overall, monotherapy nimbleukin as well as the combination with multi TKIs resulted in increased immune activation and decreased immune suppression in tumors.
We also carried out additional gene expression analyses. The graph on this slide represents expression levels of key genes in the tumors of treated animals. Angiogenesis gene expression is shown on the x axis and immune cytolytic gene expression on the y axis. The combination the comparison of mice treated with vehicle shown with the black squares with mice treated with lenvatinib showed that lenvatinib treatment resulted in significantly decreased angiogenesis gene expression in tumors due to its inhibition of the pro angiogenic VEGF signaling. Mouse nimvelukin shown by the blue triangles induced higher levels of immune cytolytic gene expression compared to tumors from either lenvatinib or vehicle treated animals.
The combination treated animals shown with circles displayed even greater levels of immune cytolytic expression along with low levels of angiogenesis gene expression, suggestive of complementary immune activation and decreased angiogenesis contributing to the enhanced efficacy of the lenvatinib combination with nemvelukin, which I'll share on the next slide. Very similar gene expression data was generated with lucitanib. Next, we wanted to see how the cell expansion and gene expression profile translates to tumor control in vivo. Shown on this slide are data on the anti tumor efficacy lucitanib combination in a poster presented at AACR in 2020. Nembleukin significantly enhanced the anticancer responses in combination with lenvatinib.
As shown in the graph on the left, the combination displayed with the purple circles resulted in a synergistic effect on tumor growth inhibition compared to either monotherapy. The graph on the right shows 50% tumor free survival in these same animals treated with the combination, showing again a nice synergistic efficacy. All animals that exhibited a complete response were protected from rechallenge with the same mouse tumor cells suggestive of immunological memory. In addition to our studies with lucitanib and lenvatinib, we also studied nemvelukin in combination with a mouse surrogate of befacizumab, which is a selective inhibitor of the angiogenesis factor VEGF. Like lucitanib and lenvatinib, combination with this anti VEGF antibody showed enhanced mouse anti tumor efficacy compared to either monotherapy.
Now let's focus on the 3rd combination approach that we are actively exploring with nembleleukin with standard of care chemotherapy and radiation therapy. Chemotherapy and radiation are mainstays of cancer treatments and there are many studies that have shown that immune like T cells and NK cells contribute to the activity of these therapies. There are preclinical examples where the response to chemotherapy can be blunted by depleting CD8 T cells, which further highlights the potential for interplay with the immune system via immunogenic cell death. In addition to inducing immunogenic cell death, chemo and radiation therapy can have counterproductive effects on the anti tumor immune response, including decreased lymphocyte counts and even increasing immune suppression by increased numbers of regulatory T cells in tumors. Nembilukin, which expands CD8 T cells and NK cells with minimal effects on immunosuppressive regulatory T cells may offer enhanced complementarity to radiation and chemotherapy by augmenting the positive effects with the potential to counteract the negative effects of these therapies on the immune system.
To that end, we are not only testing these combination approaches within research at Alkermes, we have ongoing collaborations with the leading academic institutions NYU and MD Anderson, leveraging specialized translational mouse models with initial data expected later this year. As we continue to advance monotherapy nembleukin as well as the combination with pembrolizumab clinically, we continue to research how we can harness the tremendous potential of nembleukin across a broad range of combinations and tumor types. Our internal research as well as the multiple preclinical collaborations highlighted on this slide are aimed at identifying and prioritizing the most promising novel combinations with nemvelukin. In addition, in these studies and in a dedicated effort with the University of Pittsburgh, we will continuously evaluate and strive to identify biomarkers associated with nivolukin activity. You've seen how we have leveraged preclinical research to shape the clinical development path for nemvelukin with the advancement and early testing in our clinical studies both as monotherapy and in combination with pembrolizumab.
Looking ahead, we are encouraged by the promising clinical preclinical data observed with the combination of nemvelukin with multi TKIs like lenvatinib and believe that these data support moving forward with a combination clinical study. We continue to evaluate combinations including radiation and other selected anticancer agents with the expectation that you will see additional combination clinical studies emerging based on demonstrated scientific rationale as the nemvelukin clinical development strategy continues to expand, especially as we pursue clinical collaborations with partners. Thank you very much for your attention today. Now Josh, a Principal Scientist in Oncology Research will tell you about another exciting engineered cytokine program focused on harnessing the potential of IL-twelve.
Good morning. My name is Josh Heiber. I'm a principal scientist and have been in Alkermes for just about 4 years. I received my PhD in microbiology and immunology from the University of Miami and then spent a few years as a postdoc at St. Jude Children's Research Hospital.
I've always been interested in finding new therapeutics for oncology and have worked in several therapeutic modalities, including oncolytic viruses and CAR T cells. And upon joining the team at Alkermes, I've had the opportunity to work in immunomodulatory cytokines. It is my privilege to lead a fantastic team of protein engineers, pharmacologists, analytical scientists, development personnel and others as we interrogate a really exciting biology IL-twelve. And so if we go to the next slide, we just finished hearing about another engineered cytokine that we've developed, nemvelukin alpha, which is a prime example of our capabilities. In creating that molecule, we took a well validated biology in IL-two and developed a differentiated version of the molecule designed to harness its therapeutic potential and allow for broader clinical utility.
We intend to do the same thing with IL-twelve, a powerful immunomodulatory cytokine. So let me introduce IL-twelve. IL-twelve is a heterodimeric cytokine comprised of P35 and P40 subunits, the red and green structure you see here on the cell on the right. These subunits are covalently linked by disulfide bond and then secreted from the cell. Upon secretion, IL-twelve can exert its function on both the innate and adaptive immune systems, which include NK and T cells and potently stimulate these cells to drive production of interferon gamma, which can have a variety of anti tumor benefits, including direct tumor cell killing, increasing of antigen processing machinery, decreasing of the extracellular matrix remodeling and inhibition of angiogenesis.
So you can understand why many players in the biopharma industry are interested in harnessing this powerful biology associated with IL-twelve. The use of systemic IL-twelve, however, has been limited by severe toxicity, including the development of a potentially lethal inflammatory response. Given the strong biologic potential of IL-twelve, many players in biopharma are focused on trying to develop strategies to address this toxicity and harness this biology, primarily by driving activity into the tumor. There are a number of approaches being implemented to attempt to achieve this, such as gene therapy or electroporation. However, this creates a situation where the doctor needs to find the tumor, which can limit its clinical utility.
So we propose a strategy that is designed to address the delivery challenges associated with intratumoral approaches and avoid the toxicities associated with systemic administration. Our approach is to build a self assembling tumor targeted IL-twelve molecule. In order to assemble this molecule, we first needed to split it apart. We split IL-twelve into its 2 components, P35 and P40, thereby functionally inactivating the cytokine. However, splitting these subunits apart created 2 new engineering challenges that of protein stability and protein affinity.
P35 is an inherently unstable protein. In fact, in the cell p40 acts to stabilize and assists in the proper protein folding for p35. In response to these challenges, we embarked upon both computational and rational design protein engineering approaches and identified unique mutations in P35 that allow us to produce a molecule that meets our developability criteria. In addition, we needed to reengineer the interface between P35 and P40 to recover the affinity that is which the strength that these molecules bind together. The affinity of covalently linked IL-twelve is infinite, essentially they never fall apart.
But when you split the subunits apart, while they do stick back together, this interaction was not strong enough drive the kind of pharmacodynamic response that we were interested in developing. By applying our molecular design capabilities, we were able to engineer the subunits to address the inherent stability challenges in P35 production and enhance the P35P40 affinity, thereby addressing both of these new design challenges. As I mentioned before, one of the main ways to potentially improve the tolerability of IL-twelve is through localization. So in parallel, we identified a unique tumor targeting antigen and generated proprietary antibodies. It's important to note that in tumors, certain proteins can be up regulated.
You can use this differential level of expression to drive your molecule into the tumor via targeting. When we combine our engineered subunit payloads and our proprietary antibody, we're able to generate a toolbox of novel engineered tumor targeted fusion proteins. I'll explain how this is designed to work and how this has the potential to both address systemic toxicity and drive local activity. The first step is we inject a targeted in this case p35 molecule. If we've engineered these molecules correctly to have the kinetics we desire, we end up in a situation where you have molecule accumulation in the tumor, while you have rapid systemic clearance of the molecule.
After a predetermined amount of time based on these kinetics, the systemic level of the first molecule is significantly reduced. And at this point, we can then administer the 2nd molecule, which would undergo a similar process by which it disperses through the body and accumulates in the tumor. When both of these subunits arrive in the tumor, they can self assemble into functional IL-twelve and driving IL-twelve pharmacodynamic response. This strategy avoids the systemic toxicity because you never have a fully assembled IL-twelve complex in the system. And through the use of targeting, we aim to localize and drive this response into the tumor.
The next question is, can we make this happen? In this experiment, we took our tumor targeted IL-twelve subunits and we radio label them with zirconium-eighty nine. These were then injected into the tail veins of tumor ring mice and then using PETCT imaging, we can observe the kinetics in both the blood and the tumor. The molecule on the left is what we would consider to be a fast molecule. It has fast serum clearance while being retained in the tumor, the dashed and solid lines respectively.
The first molecule with these kinetics would allow the tumor to serum window to open more quickly. We believe this could be advantageous because from a patient perspective, we want to try to keep that window as short as possible between the 2 injections, 2 injections. The molecule on the right by contrast is a molecule with slow serum clearance. This actually could be beneficial as it potentially allows for better accumulation in the tumor. As designed, you would have a fixed level of molecule A at a given point driving and driving the maximum amount of molecule B into the tumor will allow for more assembly to occur, thereby potentially achieving a stronger response.
Not only have we looked at the kinetics of these molecules, but in the next slide, I'm going to show some representative images from the same study. I'll point out here that we're introducing one of our control molecules, in this case, a non targeted single chain IL-twelve, essentially the molecule that we're working to improve. And you'll see here this year and in further slides. What's important to note is that the control molecule for all intents and purposes does not accumulate in the tumor. However, in the panels in the middle and the right, you can see quite clearly that our targeted subunits are accumulated and retained as these images were taken 72 hours post treatment in the tumor.
Observing our expected tumor and serum kinetics gives us confidence in our design concept. This data was further quantified on the right. We then took this to the next step and attempted to see do these molecules function. To do this, we leveraged a humanized NCG model. This was a model in which we took immunocompromised mice and we treated them with human PBMCs.
After a 2 week incubation, these mice have been populated with an activated T cell compartment that should be responsive to IL-twelve. And in fact, you see that there is a baseline activity in our vehicle treated animals and our single chain non targeted molecule drives a pharmacodynamic response. So we know that the system is in fact responsive to IL-twelve. What's most exciting is that this is the first time that sequential administration of our subunits has resulted in a pharmacodynamic response as measured by interferon gamma. What's also very interesting is that we see a dose response and what's particularly exciting about this differential level of gamma that we observe is the difference in dose is represented by approximate 4 hour delay after administration of the first molecule.
And this is in fact the dosing strategy that we've tested in our current proof of concept CDX study where we are testing the full concept of targeting and assembly in humanized tumor bearing mice. In conclusion, we have successfully engineered our tumor targeted IL-twelve subunits fused to our proprietary antibodies. In preclinical models, we have demonstrated that these tumor targeted subunits are retained in tumors. We've demonstrated that sequentially administered subunits can assemble to become functional and we have completed humanization of these antibodies allowing us to generate our lead candidate molecule sequences. Currently, we're in the process of characterizing the list of lead candidates and reading out our preclinical proof of concept study with the goal of initiating cell line development in the latter half of this year, which is a precursor to driving toward IND enabling talks and candidate nomination.
Thank you, Josh, for the interesting presentation on split IL-twelve. I will now shift to the neuroscience and let's start with our HDAC platform and its role in to synaptogenesis and synaptic dysfunction, followed by explaining the biological rationale for selective targeting of HDAC inhibitors for CNS disorders. You will hear how we are designing CoRes selective HDAC inhibitors, which can improve synaptogenesis. You will also hear about the first development candidate from this platform, ALKS 1140. And finally, I will give you a glimpse into our FTD GRN program.
So let's start with looking closer at the synapses. The brain is made up of 1,000,000,000,000,000 synapses. They are a major point of communication between neurons and they do constantly change. New connections are formed and others are eliminated. This process is fundamental for learning and memory.
In the center, you can see a neuron, and each neuron has thousands of dendritic spines that receive information through synaptic connections with axons from other neurons. Much of the synaptic plasticity is happening in the dendritic spines. Reduced spine density, as you see on the right, has been implicated as the primary mechanism of synapse loss and it's common in many neurodegenerative disorders, such as Alzheimer's disease and also in some neurodevelopmental disorders, such as Rett syndrome. And actually, many neurological disorders are characterized by synaptic pathology. This includes that they manifest synapse loss, they have an abnormal density of dendritic spines and an aberrant synaptic signaling and plasticity.
Therefore, targeting the synapse may slow progression and preserve cognitive and functional abilities. This gives us opportunities to target a large number of indications as you see below, ranging from neuropsychiatric disorders at the left to neurodegenerative and neurodevelopmental disorders in the middle and to the right. And this includes a subset of autism spectrum disorders in which actually many manifest a reduced spine density. In addition, recent brain imaging with SV2A PET tracers have shown loss of synaptic density in several neuropsychiatric and neurodegenerative disorders. Synaptogenesis or synapse formation is under epigenetic control.
It has been shown that knockout or inhibition of histone deacetylases, HDACs, increase the number of synapses. Conversely, overexpression reduces the number of synapses. So how do inhibitors of HDACs function? They enhance the acetylation of histones. This opens up the chromatin and the DNA, which is wound around the histones becomes more accessible.
This drives the transcription of multiple genes associated with synaptogenesis. Many classical HDAC inhibitors, which are used in oncology, to target a larger set of these 18 HDAC family members, as you see it on the left. These compounds have been limited by hematological toxicities and low brain exposure. This has precluded them from being applied in chronic neurological conditions. Class I HDACs do not work on their own.
They function in association with the multi protein complex, which determine their activity. So on the right, you see the corest complex. It is 1 of 6 known co complexes with HDAC1 or 2. It is acting directly in repression of prosynaptic genes in neuronal tissue. With this biology established, the challenge shift now to molecular design.
How can we create HDAC inhibitors that are prosynaptic and devoid of the challenges I mentioned before? Alkermes has designed HDAC inhibitors that bind to HDAC12 specifically when in the cores complex with a high selectivity against other co repressor complexes. We have achieved this selectivity in several ways. One is to utilize a specific pocket available only in HDAC1 and 2. You see this by the green molecule reaching down in a pocket on the lower right end of the blue HDAC protein.
We have 3 design goals for our HDAC inhibitors used in neurological conditions. Firstly, we want to selectively inhibit the HDAC co res complex. Secondly, we want to demonstrate favorable hematological safety. And thirdly, we want to have a desired brain exposure. Our first development candidate from this platform, ALKS 1140 was nominated last year.
ALX1140 achieved the design goals we set up for CNS focused HDAC inhibitor. It has an 80 to 2 50 fold selectivity versus other HDAC Class I complexes. It has shown minimal hematological effects in in vitro and in vivo preclinical assessments. It has a high brain permeability with CSF to plasma ratio of around 1 in several preclinical species. We are assessing our HDAC inhibitors in a rational, stepwise fashion, molecularly, structurally and functionally.
So let's start with the molecular aspect. If you look at the graph on the left, we are first assessing target engagement by measuring the increase in histone acetylation. In the second step of our molecular assessment, we are measuring the increases in proteins related to synaptogenesis. In particular, we are looking at the overlap between presynaptical SV2A and the postsynaptical PSD95 to assess an increase in the number of synapses. We're also evaluating the overlap of PSD95 with phosphorylated TRACK B to assess activated dendritic spines.
In the 3rd graph, we are measuring the increases in dendritic spines before and after treatment. And last but not least, functionally, we're looking at the restoration of brain function by evaluating the long term potentiation or LTP. Let us now look at some of the data for ALKS 1140. Okay. So let us start with the molecular assessment.
ALKS 1140, given once daily to normal mice for 14 days, increases the number of synapses by 20% to 30%, measured by the overlap of the pre synaptic and postsynaptic proteins, as seen in the left hand panel. In the middle panel, it shows similar increase in activated dendrites by measuring the coincidence of PSD95 and phosphotracB. So let us now go to the structural evaluation. In the left panel, you see the increased spine density from administering ALKS 1140 for 28 days. Again, the magnitude of the increase is between 20% to 30%.
In the right hand panel, we have monitored the spine density after the last dose. It does persist for a few days, but after a week, the spine density is back to baseline. And this indicates a reversibility and that an HDAC inhibitor needs to be on board for sustained effect. Let us now look at the functional assessment of ALKS 1140. Here in the form of an increase in long term potentiation, which can be seen as an increase in synaptic efficacy and is commonly considered a mechanism of learning.
If you look on the left hand panel, we first measured LTP in normal wild type mice and you see an improvement in the field excitatory postsynaptic potential or FEPESP with increasing doses of ALKS1140. This measure shows that postsynaptic neuron is more likely to fire an action potential. Next, on the right hand side, we have used transgenic 5x FAD mice. These mice have 5 gene mutation linked to Alzheimer's disease, which significantly reduces their baseline LTP. It is illustrated in the middle graph, where the black trace reflects the 5x FAD mice at baseline and the gray trace at the top shows the LTP for normal wild type mice at baseline.
If we now give ALKS 1140 to the 5x FAD mice, we see an increase in LTP shown by the greenish trace and we see a restoration of synaptic efficacy getting closer to what we see in wild type mice. And you can see this summarized in the bar graph on the right hand side. So now let us go to our clinical plans. We are focusing on indications that share a common pathophysiology of synaptic dysfunction in the hippocampus with deficits in cognition as the core characteristic. Initial clinical focus is planned for rare and orphan diseases with a potentially expedited development pathway.
We plan to select lead indications based on preclinical and human biomarker data among a set of neurodegenerative and neurodevelopmental indications, which are listed on the right. We plan to start our Phase I testing in health and volunteers this year. In parallel, we're initiating a Phase 0 biomarker study in patients with neurodegenerative and neurodevelopmental diseases to inform our indication selection. After the SAD MAD, we plan to run a proof of pharmacology basket study in selected neurodevelopmental neurodegenerative disorders. We will assess the effect of ALKS 1140 on biomarkers in patients to inform indication selection for our proof of concept study.
Let us now move to our next HDAC program. As I mentioned earlier, we have a select set of HDAC inhibitors that also increase the levels of the GRN gene. We're developing those HDAC inhibitors for frontotemporal dementia with mutations in the GRN gene. Frontotemporal dementia, or FTD, is the most common form of dementia for people under age 60. It is caused by degeneration of the frontal and or temporal lobes.
FTD patients demonstrate severe synaptic deficits, And there are about 60,000 people in the U. S. With FTD and currently there are no available therapies. FTD GRN is caused by mutation in 1 of the 2 GRN gene alleles And this results in that carriers exhibit low levels of the progranilin protein. And about 6,000 people in the U.
S. Are having FTD with a known mutation in the GRN gene. And the average age of onset is about 56 years with a 6 year median survival rate. It has been shown that specific HDAC inhibitors can increase programmoly in vitro. And based on preclinical data, it has also been suggested that an increase in programmolyne levels can be beneficial for a broader patient population with the TDP-forty three pathology.
Numerous studies in human neuronal cultures and transgenic animal models suggest that increasing levels of the programming protein in FTD GRN model systems can help rescue pathology. So we have designed a subset of HDAC inhibitors that not only improve synaptic function, but also increase the levels of GRN gene and the corresponding programmulin protein. So on the left hand panel, you see an increase in the GRN gene expression in a human cell line with a tool compound, RDC274,307. In the middle panel reflects an increase in the corresponding pro granuline protein. And then on the right hand side, you see an increase in total spine density by the same compound in wild type animals.
So to summarize, we have preclinical HDAC inhibitors that both increase progranulin levels and improve spine density and ultimately synaptic function. So let us now look at our overall HDAC portfolio. We have a rich portfolio of diverse selective HDAC inhibitors. In neuroscience, ALKS 1140 is being developed for orphan indications in neurology. And behind it, we have HDAC inhibitors that we are positioning towards non orphan indications.
In addition, we do have a program in oncology with HDAC inhibitors exhibiting a different selectivity profile compared to our neuroscience HDAC inhibitors. These HDAC inhibitors also have a different profile than the current oncology HDAC inhibitors on the market, And you will hear more about those at a later date. And with that, I hand over to Brian, who will give you an overview of our Orexin II agonist program. Thank you.
Hello. I'm Brian Raymer and I'm the Senior Director of Research Project Leadership and Strategy at Alkermes. I lead research programs teams to identify clinical candidates for oncology indications and central nervous system disorders. The teams include scientists skilled in molecular modeling, medicinal and synthetic chemistry, DMPK, biology, pharmacology and toxicology among other drug discovery disciplines. Previously, I served in project leadership, medicinal chemistry, chemical biology and process chemistry roles at Pfizer and Novartis.
I'm a graduate of St. Olaf College and Harvard University and I'll be sharing our team's efforts towards the orexin-two receptor agonist for the treatment of narcolepsy and other sleep disorders. By way of introduction, abnormal neurotransmission of orexin in the brain is seen with patients with sleep disorders. Orexin also known as hypocretin is a neuropeptide produced in the hypothalamus. In the figure on the right, we're showing how Orexin neurons promote wakefulness and modulate reward pathways.
Orexin controls sleep and arousal as represented by the red arrows by stimulating the release of neurotransmitters that promote alertness such as histamine, serotonin and norepinephrine. Orexin axon 2 receptors, the orexin 2 receptor, which impacts the wakefulness pathways as shown in the green arrows on the right and the orexin 1 receptor which modulates reward pathways as shown with the purple arrows on the right. In narcolepsy and other sleep disorders, lower orexin levels lead to inconsistent neurotransmitter release resulting in sleep lapses and poor regulation of REM sleep. Now narcolepsy is a chronic neurological disorder characterized by daytime sleepiness and sudden transitions into sleep. It affects over 200,000 people in the U.
S. And over 3,000,000 people globally. Approximately 70% of narcolepsy patients have narcolepsy type 1 and that condition is distinguished by the presence cataplexy, a sudden muscle weakness triggered by strong emotions and low or no orexin in the brain. Currently approved medications treat symptoms but do not address the underlying orexin deficiency. Additionally, stimulant medications often are associated with potential abuse and safety concerns, including effects on heart rate and blood pressure.
Overall, the combined medical need in narcolepsy and the clear association of Orexin with narcolepsy and sleep disorders made this an attractive drug discovery program for Alkermes. Recent identification of Orexin 2 receptor agonist show that they may have utility as replacement therapy for no or low orexin levels in stimulating the downstream release of wake promoting neurotransmitters. They would have potential applicability in narcolepsy and other indications with excessive daytime sleepiness, fatigue or attention issues. Additionally, selective orexin 2 receptor agonist may provide improved safety over currently available therapies. Overall, we felt that while the clear medical need and clear biological mechanism were attractive and the identification of nonpeptidic selective orexin 2 receptor agonists were reassuring, we knew that the chemistry needed to develop small molecule agonists was not going to be easy.
In the figure on the right, we show the binding of the orexin peptide to the orexin 2 receptor and designing a brain penetrant small molecule to drive signal transduction similar to the native peptide would likely be more challenging. But we felt the compelling biology and the link to the patient need would be worth the risk. So therefore, we work to develop the best in class molecule designed to mimic the potency and performance of the endogenous peptide orexin 2 receptor agonist with an orally bioavailable therapy. We wanted a compound that would possess a favorable half life and have a PKPD profile that would mirror the natural wake cycle. We also wanted to avoid safety risks associated with stimulant medications.
Our design goals at the start of the program was to provide a differentiated orexin 2 receptor agonist to address the unmet medical needs for the patients. We wanted to show robust efficacy with our molecule showing increased wakefulness duration and cataplexy control. We wanted to have convenient dosing, a once daily oral medication and a dose that would allow 8 to 12 hours of wakefulness with no later insomnia. And we also wanted favorable tolerability with a reduced risk of heart rate and blood pressure effects seen with stimulants. Now I'd like to talk to you about Alkermes lead orexin candidate, RDC-two hundred and sixty four thousand one hundred and seventy seven, which I'll abbreviate as 177 in certain instances and how it demonstrates potency superior to the orexin peptide in preclinical studies.
The figure on the right shows the activation of orexin-two receptor expressing histamine neurons with the y axis showing a change in membrane potential in millivolts and the x axis showing a increase in concentration from left to right in nanomolar on a logarithmic scale. The red squares represent the data points for 177 and the black circles represent the data points for a synthetic orexin B peptide. As you can see in the figure on the right, application of 177 induced a robust concentration dependent increase in neuronal excitability in rodent brain tissue. And by the leftward shift of the red left, you'll see about a 10 fold increase in potency of 177 compared to orexin B. So we feel that 177 demonstrates a promotion of prolonged wakefulness in a preclinical in vivo study, in this case a rat pharmaco EEG model of cortical arousal.
In the 4 panels in the figure below, we see from left to right a dose of the vehicle, 1, 3 or 10 mgs per kg of RDC-two hundred and sixty four thousand one hundred and seventy seven. For each individual panel, time is represented on the x axis and the frequency in hertz from the EEG study is on the y axis. I'd especially like to direct your attention to the gamma bands in the upper portion of the figures and the theta and delta bands on the lower portion of the figures as we move left to right. Here we can see a dose dependent increase in the gamma power as represented by the increasing presence of the red color that translates to an increased amount of wakefulness and the increased amount of dark blue on the lower theta and delta bands indicate a relative lack of sleep activity in this model system. Overall, we feel we're showing a dose dependent increase in weight duration with RDC-two hundred and sixty four thousand one hundred and seventy seven.
Now we also can show a dose dependent increase in both exposure and wakefulness and Alkermes has a long history of showing PKPD or pharmacokinetic pharmacodynamic relationships with drug entities. Here, we're demonstrating a strong PKPD relationship in the rat EEG model. On the left for the PK is the plasma concentration on the y axis, on the right with the PD, that's the percent wakefulness time and both axes have the same time axis for the x axis. You can see going from the 0.3, 1, 3 and 10 mg per kg lines, which are represented by blue, yellow, pink and green, you'll see an increase in the plasma concentration at increasing doses and a concomitant increase in the percent wakefulness time at those same doses. So with this strong PKPD relationship, we think this suggests the potential for a low human dose and a low drug burden.
Additionally, in similar studies, 177 did not adversely elevate heart rate and blood pressure in a rat hemodynamic model at pharmacologically type model, here we are looking at data from a DTA mouse model of narcolepsy, which we feel serves as a predictive disease model of narcolepsy in humans as the DTA mouse model has a degeneration of orexin neurons similar to the human condition. The figure on the left shows wakefulness as a percent change of vehicle from vehicle on the y axis at 0.1110 mgs per kg dose and the right figure shows a percent change from vehicle in cataplexy at a 0.1110 mgkg dose. You'll see in the left figure a dose dependent increase in wakefulness and on the right figure a dose dependent decrease in cataplexy. Of note, at the 10 mgkg dose in cataplexy, there are no error bars is essentially all of the animals in the study showed no cataplexy over the course of the study. So again, we feel that the DTA mouse model of narcolepsy serves as a predictive disease model of narcolepsy in humans and that we have dose
improvement dose dependent
improvements in wakefulness and decreases in cataplexy. Moving forward into the development of 177, we feel the molecule has a potential for to provide a meaningfully differentiated orexin agonist. We plan to nominate our lead candidate 177 in 2021 based on data that demonstrates a potential for robust efficacy, convenient dosing and favorable tolerability. We're developing efficient clinical strategies with early stage gates based on known biomarkers, including EEG to determine the sleep wake states. And finally, we're prioritizing the study of additional potential indications based on orexin biology, clinical feasibility and association with excessive daytime sleepiness and unmet need and such indications include obstructive sleep apnea, idiopathic hypersomnia, Parkinson's disease and traumatic brain
injury. Okay. Well done, Brian. Thank you. So that completes the lineup of presentations this morning.
I want to thank all the presenters for the quality of the work they and their teams are doing and for their preparation for today's event. So let's summarize briefly what we covered today and some of the most important new pieces of information. The overarching theme is this idea of scientific excellence melded with business excellence. 1st rate science directed intelligently to programs with high potential return on R and D investment, all happening within the context of a business focused on cost efficiencies and profitability. Have a $1,000,000,000 top line, proven R and D and commercial capabilities, a pipeline with growing visibility and a focus on building profitability.
We believe that as all of this becomes clear, the valuation of the company is going to reflect it. An important part of today was providing insight into our R and D engine, the platforms, the programs, the scientific capabilities and the management philosophy. Our particular strength is in molecular design applied to exploit opportunities that we see in validated biological pathways. Our strategy is to focus programs on designing new molecules targeting established biology rather than testing new biological hypotheses, then aggressively managing these programs in order to maximize the return on our R and D investments. And I hope that came through because it's been a key focus of ours.
As I said at the outset, we have been successful in developing good drugs and we expect to continue to do just that. So let's summarize the key updates today from the programs we discussed. Nembileukin, if it hasn't already appeared on your radar, I think now is a good time to focus on the potential value of this program. 2 important updates today in that program. 1st, monotherapy.
The expanding data set demonstrating activity of nembleukin as a single agent in patients with advanced melanoma and renal cell carcinoma. Not just single agent activity by itself, but single agent activity in patients who have failed multiple prior lines of therapy and are running out of options. The presence of single agent activity confirms the design hypothesis and helps explain why nemvelukin has the potential to be such a useful molecule in combination with other agents. And the second development today in nembleukin I think relates to subcu. The data on the cellular expansion of our subcutaneous dosing regimen, our selection of the Phase 2 dose, the expansion of the program and our first response in combination with pembro in a patient with platinum resistant ovarian cancer who was heavily pretreated.
These are 2 major milestones and stage gates for us in the program. They are highly differentiated, but it's important to note nemvelukin is performing as we designed it to. It's different than other IL-two variants and this is becoming more and more apparent. Additional data across the development program will be continued to readout throughout the year with abstracts submitted to upcoming meetings. We see nimbleukin emerging as a differentiated late stage oncology asset that will be of interest to a number of potential partners.
Building on the nemvelukin foundation, we've revealed 2 of our next engineered cytokine targets and focused on 1, our tumor targeted split IL-twelve program. Alkermes has real capabilities in this space and I believe that they're going to gain increasing recognition over time. On the CNS side, our HDAC co rest program is advancing with ALKS 1140 moving into the clinic. Synaptic function is a core area for us. This is exciting new science with strong biological rationale.
1140 expands our neuroscience portfolio to include orphan and rare neurology indications. So we see it as significant both from a scientific as well as a business perspective. We revealed our Orexin II receptor agonist program. We've been working in this space for some time. We are well aware of the other efforts in this space.
They validate the opportunity. We're excited by the maturation of the biological rationale and our ability to design molecules with attractive pharmaceutical properties, leveraging our long standing expertise in integrating PKPD relationships in brain penetration into drug design. So that was the science. Valera spent time at the outset focused on the business, the here and now of the commercial portfolio and how we see it growing with the anticipated contributions of Lavalvii and VUMERITY and how these revenues coupled with a focus on efficiency, cost management and strong governance have the potential to drive increasing profitability and value creation. So that's my quick wrap up of a good day.
Let's now move to this Q and A session and Sandy will moderate that.
Okay. Thanks, Rich. And thanks to everyone who submitted questions during the presentation portion of the day. I have a couple queued up here. I'll do my best to group these by topic to make it more efficient.
So our first question is from Vamil Bevan at Mizuho related to nembleukin. Are you still planning to start monotherapy and combination registrational trials this year? And then Vamil has a follow-up. But Jess, do you want to take a first crack at that one?
Sure. Thanks Sandy for the question. Yes, we are continuing to progress our programs forward. As you can see with our recent approval of the orphan designation with mucosal melanoma, we are currently engaging with the health authorities such as the FDA and planning meetings to start those upcoming registrational trials in both mucosal melanoma and CPI previously treated and progressed patients, as well as further engaging and planning for additional regulatory interactions as it relates to the combination therapy with pembrolizumab in the hard to treat platinum resistant ovarian cancer.
Great. Thanks, Jess. His follow-up is, can you provide a little more detail on the liver safety data to date? You mentioned ALT, AST increases were any of those 3, 5, 10 times above the normal range? Were there any associated elevations in bilirubin or other manifestations?
Yes, that's also a great question and I'll give additional context of that data here. So as we think about it with monotherapy activity, our most of the great events for AST and ALT elevations were grade 1 and grade 2, approximately 20% of the events were of grade 1 and 2. We only had less than 10% of grade 3 or higher related events in this and the majority of these events were transient in nature. Additionally, when we think about combination therapy, we didn't see any additive toxicity that of what you would see with pembro alone with regards. But I think it's important to note as well, all of these patients were late stage advanced disease as well were heavily pretreated.
Okay. Thanks, Jess. Next question is from Paul Matteis at Stifel. Can you talk about the real world advantages of subcu administration? Will patients actually use this drug at home or will pretreated patients still be getting therapy administered by a healthcare provider?
Sure. So, as you currently know, we just opened up that recommended Phase 2 dose and are excited by the responses that we're seeing there. And again, we'll continue to gather the safety evidence. Currently, the drug is actually administered in the clinic as an injection. But as we continue to evolve the program and mature the data and understand the safety profile even more, we will look at opportunities and how best to explore.
I think as we think about subcutaneous dosing in general versus having to sit in a chair and have an IV administration, it's the flexibility for the patient. And again, I think most importantly, we are the only IL-two variant that's actually being explored with regards to the subcutaneous dosing, so a key differentiating feature of our molecule. Great.
Thanks. And then we have we've gotten a couple of questions related to renal cell carcinoma. Can you speak to the lag factor in confirming the 2 RCC responses? Are they both unconfirmed still?
So currently, both of them are unconfirmed still, but I think it's important to note the scan frequency. So the scan frequency with regards to the response rate is every 6 weeks. So we have to wait for that time to happen. And then addition, after the scan occurs, the radiologist has to read it and then of course the site has to enter that data. So the reason you're not seeing the confirmation yet is a bit of a lag time for all of those steps to occur.
And then the second response is literally hot off the press. So this just happened within the past week or 2. And that now we have to wait for an additional scan for that confirmation. Both of these patients, important to note, they still remain on therapy and are tolerating treatment well. So we anticipate those next scan results.
Okay, great. And then we had another anonymous question. How does nimbleukin differentiate from Nektar's program and other variants in development? Craig, do you want to start us off on that question?
Yes, sure. Thanks, Sandy. I would like to just start off by sort of emphasizing that bevelucon is quite differentiated from bed peg as well as the other IL-two variant programs in development across a number of key parameters, including its molecular design, demonstrated monotherapy activity. As Jes has said, the potential for subcu dosing and our overall clinical development strategy. So I'm going to ask Heather to comment on the molecular design and the PK and PD profile, and then Jess can weigh in on the clinical differentiation.
Okay. Thanks, Craig. I'll start out with the molecular design. As we've shown you, nembleukin is a stable covalent fusion of circularly permuted IL-two fused to the alpha receptor of IL-two, utilizing the human protein sequences. Nembleukin does not require pegylation to modify its activity and it retains full potency for the intermediate affinity IL-two receptor.
Nembleukin is also intrinsically active upon systemic entry and doesn't require any metabolic activation to and also doesn't release into IL-two during the administration and resident time in the body. From a pharmacodynamic perspective, we've demonstrated greater magnitude expansion of CD8 T cells and NK cells relative to regulatory T cells in general. And then in comparison to high dose IL-two, for instance, or bempeg, nembellukin has demonstrated equivalent or greater expansion of those same effector cells with minimal expansion of regulatory T cells, unlike IL-two and bempeg, which showed greater fold increases in regulatory T cells in the periphery.
So, I guess I'll round it out for you. I think clinically, what's really the differentiating features that I see here is, 1, that monotherapy activity that we're seeing in both melanoma and renal cell carcinoma are critical and in the broad utility of this drug. We talked about to the subcutaneous dosing being flexible and as Heather just shared, the pharmacodynamic activity now translating in some clinical activity with that meaningful response that we're seeing right now in the platinum resistant ovarian cancer patient. And I think lastly, as we think about it, it's our clinical development strategy. So we could have started our development strategy and doing it as an add on therapy to already standard of care.
But where our focus is, is unmet needs where the patients need the therapies most and there's relatively limited therapy options for them. One of those being of course in the CPI failed or progressed patients and mucosal melanoma. And then secondarily with the platinum resistant ovarian cancer in the space in which PD-one inhibitors are not approved and actually have failed. And so we're encouraged by those results. So when we think about it, that monotherapy activity, the differentiation with the subcu dosing and then lastly, this clinical development strategy, I think fully rounds us out as a differentiator.
Thanks, Jess. Next question is from Cory Kasimov at JPMorgan. Maybe for Rich, what does the ideal and Enveluca partnership or collaboration look like to you? And do you believe you have enough data interest to materially accelerate discussions at this point?
Yes, I think that you're seeing that the data are coming together really nicely. So many people in the immuno oncology and oncology space are familiar with what we're doing. And I think as the data, particularly from the subcu program begin to mature, we're going to be in a really good position for partnering. I think our view of an ideal partner or partners from 1 that can expand the program. You got a sense from both Jess and Heather about how complementary Nembileukin could be to a number of different regimens.
All by ourselves, we wouldn't be able to pursue anywhere near the total number of combinations or lines of therapy or tumor types that we want to pursue. So expanding the program is critically important part of it, both in terms of the indications as well as I'd say the geographical footprint that we're testing in. 2nd would be obviously to offload and share significant mass of the R and D spend. We've been carrying the burden ourselves for a very particular reason. We think we're building significant value with the passage of time.
But the clinical program itself, it would be great to have a financial partner that could expand the program and carry some of the weight. And then 3rd, just to maximize the commercial impact that we would have post approval. So those are all going to our calculation.
Excellent. Couple of questions related to potential study design for the potential registration studies. Can you comment on what a possible study design for nimveluconin mucosal or PROP could look like? And can you provide any color on the patient that will that saw atypical capillary leak in Artistry 2? Why don't we parse those into 2 questions?
Jess, do you want to give a first characterization of the trial and where we stand with FDA on those designs? And then we'll go to the DLT.
Sure, Sandy. So as you can or as you heard, we are currently engaging with the health authority on the design structure of our trials and aligning them for the potential registrational path. As I mentioned, the mucosal melanoma is going to be in patients with previously treated and progressed on a checkpoint inhibitor therapy. And then our platinum resistant ovarian cancer is going to be in a consistent patient profile in which we've seen the activity thus far in combination with pembrolizumab. And so, we are currently designing those trials and working closely with the health authorities for that potential alignment for registrational path to move forward.
Great. And then Jeffrey's second question was around additional color on the patient that saw atypical capillary leak in ARTISTRY 2?
Cindy, do you want me to take that one?
Yes, please, Craig.
Yes, sure. So it's important to note that this occurred at our maximum tolerated dose of 6 milligrams at Q7. It's the only case of capital leak that we've seen in the program to date. And in many respects, it was an atypical case of Kapioli Leak syndrome that occurred in a 54 year old male patient with advanced non small cell lung cancer. Important to note, this patient had bilateral pleural effusions coming onto study.
The patient also had low albumin levels coming on to study and had been treated with furosemide. On day 19, which was 12 days since his last dose of nemvelukin, he developed dyspnea, abdominal and peripheral edema. Notably, there was no hypertension. And once again, he had bilateral pleural effusions. 700 ml of pleural fluid was drained from the patient.
And this was resolved his clinical situation was resolved with single dose of furosemide. So as you can see, atypical case and the only case of Kapiolin leak that we've seen so far at the maximum tolerated dose in the subcu program.
Right. Thanks, Craig. And then Jeffrey, you said one more follow-up question. How do you plan to move the IV and subcu programs forward as you head toward registration? Will there be a point where the subcu formulation takes the lead over the IV program?
Jess, do you want to take a first stab at that and then Craig, you can jump in if you have any additional color?
Sure. Thanks, Sandy. So I find this to be a great challenge to have. I think it's important to note, we just recently expanded that recommended or we just recently achieved the recommended Phase 2 dose and opened that expansion in the early part of this year. And what you're seeing is, of the first handful of patients, the first responder there.
So we have to wait for that data to continue to accumulate and mature. And once we have more accumulation of that data and the maturity behind that data, we will work in a pragmatic path with the health authorities to find the best potential way to put the subcutaneous dose into our registrational path.
Yes. And just to add to that, I think the exciting news is that we've now seen the first response with the subcu administration. Obviously, we'll be looking to see more patients' data mature there. And if we do see further responses, we can consider potentially how to bridge from the IV to subcu. Having said that, the feedback that we've got from many of our investigators is that efficacy trumps all.
And they see that the IV administration for melanoma, especially the mucosal melanoma study as well as the PROC study is a feasible administration moving forward. So I think it's all good news. I think both IV can stand on its own, and I think we'll be looking at ways that we can now sort of allow the data to mature for subcu and then potentially look at a bridging strategy there as well.
Thanks, Craig. Now we can pivot to the Orexin program. I got a lot of interesting questions on that one. First one comes from Akash at Wolfe. This question is for Brian.
And then Akash has a follow-up. Based on your work in CNS drug lead optimization, why has it been so difficult to formulate an oral CNS penetrating orexin 2 agonist? What's the most important factor we need to consider for these types of drugs for optimal penetration in PK? And what nuances trade offs should we be aware of?
Brian,
do you have any?
Sure. Thanks for the question. Two key reasons are the difficulty in identifying non peptide agonists for neuropeptide GPCRs and the physical properties that accompany neuropeptide ligands. And this is exemplified by agonists at peptides such as orexin, somatostatin and korelin. It is difficult to recapitulate all the peptide interactions with a non peptide.
So the key interactions need to be identified to reduce the size of the molecule and align the properties that you mentioned such as molecular weight, lipophilicity and polarity with a brain penetrance physical chemical profile. Our overall approach was to keep the key interactions and trim away any extraneous molecular features to arrive at an engineered molecular structure that allows for brain penetration. And as Marcus described in the research introduction, state of the art modeling was key to our design of molecules that activate the orexin 2 receptor and allow for sufficient brain penetration to promote wakefulness.
Great. And the follow-up is, on the PAC-nine twenty five ID data, we've seen short drug half life and immediate drop in sleep latency mean wake time in healthy volunteers post infusion. Why do you think this is happening? Is it related to MOA or PK? And are there difficulties with engineering OX2 receptor agonists with longer half life or related to OX1, are you some other off target issue?
So I'll pass that back there. I'll let you to it.
Thanks. I'll try to unpack that question. Thanks, Sandy, and thanks for the question. Based on the publicly available data, we believe this is the response that is described in the question is likely due to a fast clearance of TAK-nine twenty five. As you may know, Takeda proposes that the wakefulness response is linked to time over efficacious concentration.
So this would be in line with that hypothesis. Engineering molecules a longer half life is a typical medicinal chemistry challenge. We feel that 177 has sufficient metabolic stability and potency to provide wakefulness with a once daily dose. And based on our preclinical data in RAT, we don't see adverse blood pressure increases or at pharmacologically relevant doses and we plan to monitor these other toxicological responses that are seen in preclinical and clinical studies is warranted. So we think we're on the right track here based on the question.
Thanks, Brian. A question from Umer Raffat at Evercore ISI, also on the Orexin program. What are the timelines for Orexin agonist entering Phase 1? Marcus, do you want to jump in on that one for us?
Sandy, happy to do that. So we are in our orexim program currently in the preclinical phase, and we'll be nominating this year. And then we are hoping to be in the clinic in end of 'twenty two, beginning of 'twenty three.
Thanks, Marcus. And then we have one more question on the orexin program from Jason Gerberry at Bank of America. What is your view as to whether correcting orexin deficiency can improve sleep architecture versus offering clinical benefit on daytime alertness? Brian, do you want to take a crack at that and Craig then perhaps you can offer your clinical perspectives?
Sure. That's I think that's a really interesting question and one that we're looking into preclinically. I can't comment on our data flow right now, but essentially we'll be modulating both the orexin system and the downstream neuropeptide system overall in the brain. And so the hope is that there's some residual effect past wakefulness on the sleep architecture. I think that's to be determined.
And certainly from the clinical picture, we don't have a strong picture on that yet. And pre clinically, that story is still developing on the molecular biology level.
Yes. And I mean, just to add from a clinical perspective, I think it will very much be informed by the preclinical work that Brian and the team will be embarking on. So but I think there's a lot of potential there.
Thanks, Craig. I have a couple of questions on the HDAC program. This one's from Akash at Wolfe. Marcus, these will be for you. There's a few of them embedded in here.
I'll read them all and then we can unpack them as we go. The published preclinical paper showed efficacy after 2 week treatment of the HDAC inhibitor in a mouse model. Do you think it's possible as the neurodegenerative disease progresses, the pre synaptic efficacy may not be maintained? Had you studied the duration of effects as the disease progresses in the animal models? What preclinical safety work have you done to derisk hematotoxicity?
What degree of selection of HDAC12 over HTAP-three gives you confidence that the CMPD will have sufficient safety margin in patients? I'll have to get through there. Marcus, let me know if you need me to repeat any of the questions.
Thank you, Sandy. I'll try to unpack them 1 by 1. So we have studied the spine density up to 4 weeks in our preclinical mouse models and seen a sustained effect during that time period. So having said that, in neurodegenerative diseases, there is a continuing loss of continuing loss of neurons, and eventually, there will be fewer synapses. So what we anticipate from our HDAC inhibitors in neurodegenerative indications is a delay in the decline of cognitive abilities.
And coming to the safety question, so in our in vitro assays, we have more than 100 fold selectivity versus HDAC3 and all the way to HDAC11. And the highest concentration we have tested is 30 micromolar in all of those. And all of those IC50s are above that for HDAC3 to HDAC11. And also during our optimization work, we have routinely tested our molecules in colony forming units or CFU assays to assess the hematological safety profile. And then we also have in vivo done up to 14 day non GLP safety assessment studies in 2 species.
And we are currently doing the 28 day GLP safety study.
Great. Thanks, Marcus. Here's another one on the HDACs from an anonymous user. How does your approach differ from the HDACs used in oncology?
Thank you, Sandy. So the HDAC inhibitors on the market for oncology, they do inhibit a broader range of HDACs, and this makes them also prone to have more side effects. And one example are the hematological side effects, and they're also having poor brain permeability. Alkermes HDAC inhibitors are much more specific in their inhibition of HDACs and that they're focused on inhibiting only 12, as you heard. But not only that, HDAC12 do not function on their own.
They're part of the protein complexes. So our CNS HTAC inhibitors are unique in that they selectively inhibit HTAC12 when bound to the co rest complex, but not when bound into other complexes. So this has resulted in that the compounds do have a favorable profile preclinically for hematological side effects, for example. And in addition, Alchemists compounds are designed to be brain
portfolio, here's a question for Josh. How does IL-twelve differ from IL-two?
Thanks, Andy. It's a great question. It's true that both of these molecules ultimately lead to interferon gamma but they get there in unique ways. So IL-two signals through STAT-five and IL-twelve signals through STAT-four. I like to think of IL-two is more of an expander first and an activator second and IL-twelve, I think, really is an activator first and expander second.
And lastly, IL-twelve can drive a kind of diverse array of function, which includes production of TNF alpha, things like IP10.
Great. Thanks, Josh. Okay. Got a few more questions to get through. This one is for Richard on Libolvii.
Can you speak to whether the FDA has inspected the manufacturing site for Libolvii? What's your confidence level that there won't be a REMS? And given AbbVie's projections for $4,000,000,000 of VRAYLAR sales, what sort of peak sales can Libalvi achieve? And that one's from Jason Gerberry at Bank of America. Rich, do you want to start us off on that one?
Yes, sure. We manufacture Libolvi at our Wilmington, Ohio facility where we make VIVITROL and ARISTADA. So the site has been inspected many times by FDA and other regulatory authorities. It has not been inspected in the context of the Livalve NDA. We're responding to remote records requests on a written basis in this NDA.
And we're hopeful that will be sufficient through to the June 1 PDUFA date. We don't anticipate REMS that continues to be our expectation. And I don't think we'll make any peak revenue projections yet for La Balvi. Let's get it approved and launched and we'll take it from there.
Sounds good. Here's one for Blair. Any comments on the recent Paragraph IV filing on VUMERITY by Teva? If Teva is successful, how does this impact what is being laid out today in terms of R and D investment, understanding that you have a very strong balance sheet? And that's from Brandon Folkes at Cantor.
Hi, Brandon. Thanks for the question. So we launched or developed VUMERITY for multiple sclerosis. And we're really with Biogen launching into a really large multibillion dollar market. And so you can imagine that attracts the attention of a lot of generic suppliers.
And in order for them to get into the market before our patents expire, they need to try to see if they can find chinks in the armor of your patent protection. So we did receive a paragraph for certification late last year. And as per the standard course with this, what you do is we filed suit, which triggers an immediate 30 month stay. So that allows us to work through the prosecution and the procedures. And through that, we're going to vigorously defend our patent portfolio, which we feel quite good about.
I would say that to the second part of your question with regards to reduction of revenue, whether it's we have reduced revenue from HUMERITY for whatever reason or any of our other commercial programs. I'll point you back to their discussion earlier today. We're running the business in a very conservative way. We've identified a number of different efficiency opportunities that we're executing upon. And we have a number of different strategic options and levers that we can pull if for whatever reason we see a shortfall of revenue that differs slightly from what we expected in our current planning case.
So our plan is to meet our it in our current planning case. So our plan is to meet our non GAAP net income margin targets in a wide, wide range of scenarios, whether revenue is higher, whether revenue is smaller than we anticipated.
All right. Thanks, Blair. There's a couple of questions on ARISTADA. This one is from Jeet Mukherjee at Jefferies. Can you talk about how you plan to balance supporting the ARISTADA franchise while simultaneously leveraging the site infrastructure to support the Libolvii launch?
Blair, do you want to jump in?
I'm sorry, can you repeat the question?
Sorry, that was, can you talk about how you plan to support the ARISTADA franchise while simultaneously leveraging the psych infrastructure to support the Libolvi launch?
Thanks. Yes, thanks for the question. So with regards to the launch of Libolvi, as we've talked about a lot, there there's a significant amount of leverage in the business. And we have a number of shared services within our commercial organization, whether that's the patient access services or business insights, to name a few. And these groups are scaled to allow to support multiple programs.
Additionally, we're currently calling on about 60% of the targets associated with Livaldi already through our ARISTADA sales force. And we recently announced a realignment of our commercial organization to allow for really an efficient launch of LIVALVI as well as the support of ARISTADA through a single force. And so what that allows us to do is really launch in a very efficient way. We did a comprehensive review of our cost structure, as you know, over the since late last year into early this year. And we had a number of sort of core tenants.
And one of the key core tenants, in fact, the number one core tenant, was ensuring that we had the full support of the commercial team protected in a way to ensure that we have growth of our top line revenues consistent with our growth plans.
Thanks, Blair. And here is a related follow-up question on that topic. Would you use your current site infrastructure for the HDAC or Orexin programs? Would you need to build separate infrastructures to support those in a commercial setting?
No, it's a great question. It's probably a little premature to talk about where we're going to be commercializing these programs. As you've seen in the discussion today, there's a variety of different directions that some of these programs can go. And as a company, we take a very careful look at programs before we decide to enter into the commercial markets. Over the years, we've developed a large number of products and only a few of them did we decide to commercialize.
And some of those, most notably, are in substance abuse and schizophrenia and bipolar 1 disorder. And those have been really good decisions. But if you look at other areas, as an example, in multiple sclerosis, with the development of VUMERITY, we looked carefully at business opportunity there, the competitive landscape and made a decision that it would be best actually for Biogen to commercialize that on behalf of us and in partnership with us. And that's been a great decision for the business. So I think as we get further on in the development program, we'll assess that more carefully.
Sorry, Sandy, you're muted.
Thanks, Blair. This one's we have time for one more follow-up question and this one's also on ARISTADA for Blair. Can you speak to the extent to which COVID has had an impact on ARISTADA sales from Jason Gerberry?
Sure. As I mentioned earlier in the day, with COVID-nineteen, we did see disruption in the overall patient flow model in our commercial business, specifically with some of the injectable drugs. We saw a number of settings of care, both within the VIVITROL program and sort of alcohol dependence and opioid dependence as well as within schizophrenia. We saw these settings of care have a reduced patient flow. Some physicians were unavailable to their patients or some of the support staff were unavailable to patients.
And that limited the ability of this group to receive injections. And so that had a bigger impact on VIVITROL just due to the nature. These substance abuse centers are a little more unique. As you look at schizophrenia, it was a more modest impact. But despite that, we still were able to see significant growth with ARISTADA.
And a lot of that had to do, as I said earlier, with the patient, the product characteristics. The 2 month dosage form is really fits well in that treatment environment because physicians are able to perhaps interact with their patients less if that's what they choose to do. And so yes, we did see an impact, but again, I think we were able to overcome that largely due to the commercial performance of the brand.
Great. Thank you. So thanks everyone for the good questions in this Q and A session here. If we didn't get to your question or if you have follow-up questions, please don't hesitate to reach out to us at the company. And then my thanks to our panelists today for being available for Q and A as well.
Thanks very much everybody.